Method of preparing amino carboxylic acids

ABSTRACT

Novel compounds, N,N′-bis(phosphonomethyl)-N,N′-bis(hydroxycarbonylmethyl)urea and N,N,N′,N′-tetrakis(hydroxycarbonylmethyl)urea, suitable for use in preparing N-acyl aminocarboxylic acids that can be readily converted to N-(phosphonomethyl)glycine are provided. The compounds may be formed by the reaction of bis-(phosophonomethyl)urea or urea respectively with carbon monoxide and formaldehyde in the presence of a carboxymethylation catalyst precursor and solvent.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority as a divisional frompending U.S. patent application Ser. No. 09/499,699 (filed Feb. 7,2000), which claims divisional priority from U.S. Pat. No. 6,153,753(issued Nov. 28, 2000), which claims priority from U.S. ProvisionalApplication Ser. No. 60/037,775 (filed Feb. 13, 1997). The completetexts of U.S. patent application Ser. No. 09/499,699, U.S. Pat. No.6,153,753 and U.S. Provisional Application Ser. No. 60/037,775 arehereby incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates, in general, to the preparation ofamino carboxylic acids, salts, and esters, and, in a preferredembodiment, to the preparation of N-(phosphonomethyl)glycine, its salts,and its esters, wherein the method of preparation comprises acarboxymethylation step.

[0004] 2. Description of Related Art

[0005] Amino carboxylic acids are useful in various applications.Glycine, for example, is widely used as an additive in processed meat,beverages, and in other processed food stuffs. It is also used widely asa raw material for pharmaceuticals, agricultural chemicals, andpesticides. N-(phosphonomethyl)glycine, also known by its common nameglyphosate, is a highly effective and commercially important herbicideuseful for combating the presence of a wide variety of unwantedvegetation, including agricultural weeds. Between 1988 and 1991,approximately 13 to 20 million acres per year worldwide were treatedwith glyphosate, making it one of the most important herbicides in theworld. Convenient and economical methods of preparing glyphosate andother amino carboxylic acids are, therefore, of great importance.

[0006] Franz, et al. in Glypohosate: A Unique Global Herbicide (ACSMonograph 189, 1997) at p. 233-257 identify a number of routes by whichglyphosate can be prepared. According to one of these, iminodiaceticacid disodium salt (DSIDA) is treated with formaldehyde and phosphorousacid or phosphorous trichloride to produceN-(phosphonomethyl)-iminodiacetic acid and sodium chloride. Acarboxymethyl group on the N-(phosphonomethyl) iminodiacetic acid isthen oxidatively cleaved in the presence of a carbon catalyst to produceglyphosate acid. A significant drawback of this method is that itproduces as a side product three equivalents of sodium chloride perequivalent of glyphosate. Sodium chloride streams of this nature aredifficult to recycle because typically after precipitation the saltcontains significant quantities of entrapped organic matter. Suchentrapped organic matter prevents the sodium chloride from being usedfor many purposes, for example in foods or feed. Furtherrecrystallization of the sodium chloride adds cost which makes recycleeconomically unfeasible. Alternate methods of disposing of sodiumchloride without detriment to the environment are expensive anddifficult.

[0007] Franz et al. (at 242-243) describe another method in whichN-isopropylglycine is phosphonomethylated to produceN-isopropyl-N-(phosphonomethyl)glycine. In this method, theN-isopropyl-N-(phosphonomethyl)glycine is heated to 300° C. with 50%sodium hydroxide and then treated with hydrochloric acid to produceglyphosate. The severe and costly conditions necessary to cleave theN-isopropyl group represents a significant disadvantage of that method.In addition, this method also produces a significant sodium chloridewaste stream.

[0008] In U.S. Pat. No. 4,400,330, Wong discloses a method for thepreparation of glyphosate in which 2,5-diketopiperazine is reacted withparaformaldehyde and a phosphorous trihalide in a carboxylic acidsolvent to produce N,N′-di(phosphonomethyl)-2,5-diketopiperazine. Theproduct is then saponified to form a glyphosate sodium salt. The Wongmethod is limited by the fact diketopiperazine is a relatively expensivestarting material. Furthermore, the conversion of glyphosate sodium saltto the acid form or to other salts produces an undesired sodium chloridewaste stream.

SUMMARY OF THE INVENTION

[0009] Among the objects of the present invention, therefore, is theprovision of a well-defined, low-cost process for the production ofamino carboxylic acids, in general, and N-(phosphonomethyl)glycine, inparticular, and the provision of such a process in which sodium chlorideis not generated as a by-product.

[0010] In the process of the present invention, an N-acyl aminocarboxylic acid is formed via a carboxymethylation reaction. In thisreaction, a reaction mixture is formed which contains a base pair,carbon monoxide and an aldehyde with the base pair being derived from acarbamoyl compound and a carboxymethylation catalyst precursor. In apreferred embodiment, the carbamoyl compound and aldehyde are selectedto yield an N-acyl amino carboxylic acid which is readily converted toN-(phosphonomethyl)glycine, or a salt or ester thereof having thefollowing structure:

[0011] wherein R⁷, R⁸, and R⁹ independently are hydrogen, hydrocarbyl,substituted hydrocarbyl, or an agronomically acceptable cation. Ingeneral, carbamoyl compounds which are selected to produceN-(phosphonomethyl)glycine correspond to structure (II):

[0012] wherein R¹ is hydrogen, hydrocarbyl, substituted hydrocarbyl,—NR³R⁴, —OR⁵, or —SR⁶;

[0013] R² and R^(2a) are independently hydrogen, hydrocarbyl, orsubstituted hydrocarbyl;

[0014] R³ and R⁴ are independently hydrogen, hydrocarbyl, or substitutedhydrocarbyl; and

[0015] R⁵ and R⁶ are independently hydrogen, hydrocarbyl, substitutedhydrocarbyl, or a salt-forming cation;

[0016] provided, however, (1) at least one of R² and R^(2a) is hydrogen,hydroxymethyl, amidomethyl, or another substituent which, under thecarboxymethylation reaction conditions, is capable of producing an N—Hbond, or (2) R¹ is —NR³R⁴ and at least one of R³ and R⁴ is hydrogen,hydroxymethyl, amidomethyl, or another substituent which, under thecarboxymethylation reaction conditions, is capable of producing an N—Hbond.

[0017] In one embodiment of the process of the present invention,therefore, an amino carboxylic acid or a salt or an ester thereof isprepared by carboxymethylation of a carbamoyl compound. In this process,a reaction mixture is formed by combining the carbamoyl compound and acarboxymethylation catalyst precursor in the presence of carbon monoxideand hydrogen. Water and an aldehyde are introduced into the reactionmixture after the carbamoyl compound and the carboxymethylation catalystprecursor are combined and the components of the reaction mixture arereacted to generate a product mixture containing an N-acyl aminocarboxylic acid reaction product and a catalyst reaction product.

[0018] In another embodiment of the process of the present invention, areaction mixture containing the carbamoyl compound, carbon monoxide,hydrogen, an aldehyde, and a carboxymethylation catalyst precursorderived from cobalt is formed. The components of the reaction mixtureare reacted to generate a product mixture containing an N-acyl aminocarboxylic acid reaction product and a catalyst reaction product. Thecatalyst reaction product is recovered from the product mixture and thecatalyst reaction product is regenerated in the presence of thecarbamoyl compound.

[0019] In a further embodiment, the process of the present invention isdirected to the preparation of N-(phosphonomethyl)glycine or a salt orester thereof. In this process, an N-acyl amino acid reaction product isprepared by carboxymethylating a carbamoyl compound in a reactionmixture formed by combining the carbamoyl compound, formaldehyde, carbonmonoxide, hydrogen and a carboxymethylation catalyst precursor derivedfrom cobalt. The N-acyl amino acid reaction product is converted toN-(phosphonomethyl)glycine or a salt or ester thereof wherein saidconversion comprises deacylating the N-acyl amino acid reaction productto generate a carboxylic acid and an amino acid. The carboxylic acid isreacted with an amine to generate the carbamoyl compound or a compoundfrom which the carbamoyl compound may be derived.

[0020] In a further embodiment, N-(phosphonomethyl)glycine or a salt orester thereof is derived from N-acetyliminodiacetic acid. TheN-acetyliminodiacetic acid is prepared by carboxymethylating acetamidein a reaction mixture formed by combining acetamide, acetic acid, water,formaldehyde, carbon monoxide, hydrogen, and a carboxymethylationcatalyst precursor derived from cobalt. The N-acetyliminodiacetic acidis converted to N-(phosphonomethyl)glycine or a salt or ester thereofwherein said conversion comprises deacylating N-acetyliminodiaceticacid.

[0021] In a further embodiment, N-(phosphonomethyl)glycine or a salt orester thereof is derived from an N-acyl amino acid carboxylic acidreaction product which is prepared from a reaction mixture containing acarbamoyl compound selected from among ureas and N-alkyl substitutedamides, a carboxymethylation catalyst precursor, formaldehyde, andcarbon monoxide. The N-acyl amino carboxylic acid reaction product isthen converted to N-(phosphonomethyl)glycine or a salt or ester thereof.If the carbamoyl compound is an N-alkyl substituted amide, theconversion step(s) comprise oxidatively dealkylating the N-acyl aminocarboxylic acid reaction product in the presence of oxygen using a noblemetal catalyst.

[0022] The present invention is additionally directed to the certain keystarting materials used and intermediates prepared in the process of thepresent invention.

[0023] For example, in one embodiment, the present invention is directedto a compound having the formula:

[0024] In another embodiment, the present invention is directed to acompound having the formula:

[0025] In yet another embodiment, the present invention is directed toan acetamide equivalent compound selected from the group consisting ofcompounds having the formula:

[0026] wherein R¹³ and R¹⁴ are independently hydrogen, hydroxymethyl,alkyl, carboxymethyl, phosphonomethyl, or an ester or salt ofcarboxymethyl or phosphonomethyl; R¹⁵, R¹⁶ and R¹⁷ are independentlyalkyl or —NR³R⁴; and R³ and R⁴ are independently hydrogen, hydrocarbyl,or substituted hydrocarbyl.

[0027] In still a further embodiment, the present invention is directedto a compound having the formula:

[0028] wherein R¹ is hydrogen, hydrocarbyl, substituted hydrocarbyl,—NR³R⁴, or SR⁶; R³ and R⁴ are independently hydrogen, hydrocarbyl, orsubstituted hydrocarbyl; and R⁶ is hydrogen, hydrocarbyl, substitutedhydrocarbyl, or a salt-forming cation.

[0029] Further scope of the applicability of the present invention willbecome apparent from the detailed description provided below. It shouldbe understood, however, that the following detailed description andexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0030]FIG. 1 is a graph of the molar ratio of acetic acid to cobaltversus the yield of N-acetyliminodiacetic acid (XVI) under theconditions described in Example 4.

[0031]FIG. 2 is a graph of the molar ratio of acetic acid to cobaltversus the yield of N-acetyliminodiacetic acid (XVI) under theconditions described in Example 5.

[0032]FIG. 3 is a graph of the time required to regenerate a cobalt (II)salt under five separate sets of reaction conditions in which thepartial pressure ratio of carbon monoxide to hydrogen is decreased, andthe concentrations of acetamide (AcNH2) and acetic acid (HOAc) arevaried under the conditions described in Example 13.

DETAILED DESCRIPTION OF THE INVENTION

[0033] The process of the present invention is broadly directed to thecarboxymethylation of carbamoyl compounds in which strong acidco-catalysts or anhydrous conditions are not required. A preferredembodiment of this process is schematically depicted in Reaction Scheme1 in which hydridocobalttetracarbonyl is identified for convenience ofdiscussion as the carboxymethylation catalyst precursor:

[0034] As depicted, a carbamoyl compound is reacted withhydridocobalttetracarbonyl to produce a base pair of the presentinvention. The base pair, when present in a reaction mixture along withcarbon monoxide and an aldehyde (or source of aldehyde) , reacts toproduce an N-acyl amino carboxylic acid reaction product and a cobaltreaction product. The N-acyl amino carboxylic acid reaction product maythen be deacylated, for example, by hydrolysis, or otherwise furtherreacted as described elsewhere herein.

[0035] The hydridocobalttetracarbonyl which is reacted to form the basepair, may be obtained in any one of several ways. In one embodiment ofthe present invention, it is generated in situ in a reaction mixtureprepared by combining the carbamoyl compound and dicobaltoctacarbonyl(or other catalyst precursor) in the presence of hydrogen, andoptionally carbon monoxide and an aldehyde; as depicted in ReactionScheme 1, the dicobaltoctacarbonyl may be obtained by recycle andregeneration of a cobalt(II) salt which is recovered from a priorcarboxymethylation step. Recovery of a cobalt(II) salt for conversion tocobalt octacarbonyl dimer is described in Weisenfeld, Ind. Eng. Chem.Res., Vol. 31, No. 2, p. 636-638 (1992). In a second embodiment of thepresent invention, the cobalt(II) salt is regenerated using carbonmonoxide and hydrogen by conventional techniques to producehydridocobalttetracarbonyl which is combined with the carbamoyl compoundin a reaction mixture. In a third embodiment of the present invention,the cobalt(II) salt is converted to hydridocobalttetracarbonyl usingcarbon monoxide and hydrogen in the presence of the carbamoyl compoundwhich produces a reaction mixture containing the base pair; aldehyde isthen introduced to the reaction mixture to yield the N-acyl aminocarboxylic acid reaction product.

A. Preparation of the Base Pair

[0036] The base pair is formed by the reaction of a carbamoyl compoundand a carboxymethylation catalyst precursor. In general, the carbamoylcompound is an amide, a urea, or a carbamate, preferably an amide or aurea. More preferably, the carbamoyl compound is a compound having thestructure (II):

[0037] wherein R¹, R² and R^(2a) are as previously defined.

[0038] In one embodiment of the present invention, R¹ is hydrocarbyl orsubstituted hydrocarbyl, typically a C₁ to about C₂₀ hydrocarbyl orsubstituted hydrocarbyl. In this embodiment, R¹ is preferably C₁ toabout C₁₀, more preferably C₁ to about C₆, even more preferably C₁.

[0039] In another embodiment of the present invention, R¹ is —NR³R⁴. Inthis embodiment, R³ and R⁴ are independently hydrogen, hydrocarbyl orsubstituted hydrocarbyl. In general, if either of R³ and R⁴ arehydrocarbyl, it is a C₁ to about C₂₀ hydrocarbyl, preferably C₁ to aboutC₁₀, more preferably C₁ to about C₆, and still more preferably methyl orisopropyl. If R³ or R⁴ is substituted hydrocarbyl, typically it is C₁ toabout C₂₀ substituted hydrocarbyl, preferably C₁ to about C₁₀, morepreferably C₁ to about C₆, and still more preferably it isphosphonomethyl (—CH₂PO₃H₂), hydroxymethyl (—CH₂OH), amidomethyl(—CH₂N(R′)C(O)R″), carboxymethyl (—CH₂CO₂H), or an ester or salt ofcarboxymethyl or phosphonomethyl. If R² and R^(2a) are each hydrocarbylor substituted hydrocarbyl, it is preferred that at least one of R³ andR⁴ be hydrogen, hydroxymethyl, amidomethyl, or another substituentwhich, under the carboxymethylation reaction conditions, is capable ofproducing an N—H bond. In general, preferred amidomethyl substituentscorrespond to the structure

[0040] wherein R¹¹ and R¹² are independently hydrogen, hydrocarbyl,substituted hydrocarbyl, hydroxymethyl, carboxymethyl, phosphonomethyl,or an ester or salt of carboxymethyl or phosphonomethyl.

[0041] Preferably, at least one of R² and R^(2a) is hydrogen,hydroxymethyl, or amidomethyl. More preferably, at least one of R² andR^(2a) is hydrogen. If, however, R² or R^(2a) is hydrocarbyl, it istypically a C₁ to about C₂₀ hydrocarbyl, preferably C₁ to about C₁₀,more preferably C₁ to about C₆, and still more preferably methyl orisopropyl. If R² or R^(2a) is substituted hydrocarbyl, typically it isC₁ to about C₂₀ substituted hydrocarbyl, it is preferably C₁ to aboutC₁₀, and more preferably C₁ to about C₆. The substituted hydrocarbyl canbe, for example, phosphonomethyl, hydroxymethyl, amidomethyl,carboxymethyl, an ester or salt of carboxymethyl or phosphonomethyl, or(N′-alkylamido)methyl, preferably phosphonomethyl, carboxymethyl,amidomethyl or an ester or salt of carboxymethyl or phosphonomethyl. Itis possible for R² and R^(2a) to be non-identical. For example, R² canbe hydrocarbyl and R^(2a) can be substituted hydrocarbyl. In oneembodiment, R² can be an alkyl such as methyl while R^(2a) can be, forexample, an (N′-alkylamido)methyl group such as (N′-methylamido)methylor hydroxymethyl.

[0042] The carboxymethylation catalyst precursor which is reacted withthe carbamoyl compound to form the base pair may be any compositionwhich is known to be useful in carboxymethylation reactions whichgenerally contain a metal from Group VIII of the Periodic Table (CASversion). These compositions are referred to as carboxymethylationcatalyst precursors herein since the precise form of the catalystparticipating in the reaction has not been determined with certainty.Without being bound to any particular theory, however, it is presentlybelieved that the base pair itself, which is produced by the interactionof the carboxymethylation catalyst precursor and the carbamoyl compoundin the presence of carbon monoxide and hydrogen, serves as the catalystfor the carboxymethylation reaction. In any event, thecarboxymethylation catalyst precursor is preferably derived from cobaltor palladium, preferably cobalt, and still more preferably thecarboxymethylation catalyst precursor is derived from cobalt metal,cobalt oxide, organic and inorganic salts, for example, halides such ascobalt chloride and cobalt bromide, aromatic and aliphatic carboxylatessuch as cobalt acetate, cobalt propionate, cobalt octanoate, cobaltstearate, cobalt benzoate and cobalt naphthenate, and complex compoundscontaining one or more ligands such as carbonyls, nitriles andphosphines. The preferred cobalt containing carboxymethylation catalystprecursors are dicobalt octacarbonyl (Co₂(CO)₈),hydridocobalttetracarbonyl (HCo(CO)₄), cobalt tetracarbonyl anion([Co(CO)₄]⁻) or a cobalt(II) salt.

[0043] Depending upon the nature of the carbamoyl compound, the basepair may be formed in the presence of the aldehyde (or an aldehydesource which may contain water) and carbon monoxide or it is firstformed and then combined with the aldehyde source. When the carbamoylcompound is an amide such as acetamide, the reaction mixture may beformed by introducing the amide, aldehyde source, carbon monoxide, andcarboxymethylation catalyst precursor to the mixture without premixingthe amide and the carboxymethylation catalyst precursor to form the basepair; as a result, the base pair is formed in the presence of thealdehyde source. To obtain significant yields of N-acyl amino carboxylicacid reaction product when urea or a substituted urea such asbis-phosphonomethylurea is used as the carbamoyl compound, however, thebase pair is preferably formed in the essential absence of water andaldehyde sources which contain water; under these conditions, the basepair is obtained in good yield. The resulting base pair is then mixedwith the aldehyde source and carbon monoxide.

[0044] Without being bound to any particular theory and based uponexperimental evidence obtained to date, it appears that the formation ofthe desired base pair is related to the basicity of the carbamoylcompound; that is, carbamoyl compounds such as acetamide appear to besufficiently basic to produce the desired base pair in the presence ofwater and aldehyde sources which contain water whereas ureas which areless basic than acetamide do not. Stated another way, experimentalevidence obtained to date suggests (1) the carboxymethylation catalystprecursor deprotonates under the carboxymethylation reaction conditionsand forms a base pair with various species in the reaction mixture, (2)only those base pairs formed with the carbamoyl compound are productive(that is, will lead to the formation of the N-acyl amino carboxylic acidreaction product), and (3) amides such as acetamide will sufficientlybase pair with hydridocobalttetracarbonyl anion in the presence of analdehyde source which contains water whereas urea and comparable baseswill not.

B. Carboxymethylation Reaction

[0045] In the process of the present invention, the base pair which isformed is reacted with carbon monoxide and an aldehyde (or an aldehydesource) in a carboxymethylation reaction to produce an N-acyl aminocarboxylic acid reaction product.

[0046] The pressure at which the carboxymethylation reaction is carriedout may be from about 200 psi to about 4000 psi (about 1,400 kPa toabout 28,000 kPa). Preferably, the pressure is from about 1000 to about3700 psi (about 7,000 kPa to about 26,000 kPa), and more preferably fromabout 1250 to about 3500 psi (about 9,000 kPa to about 24,000 kPa).

[0047] In the carboxymethylation reaction, hydrogen or other diluentgases, such as nitrogen or helium may be introduced with the carbonmonoxide. Preferably, the atmosphere contains a significant partialpressure of hydrogen. Typically, the partial pressure ratio of carbonmonoxide to hydrogen will be at least about 1:1, preferably about 70:30to about 99:1, and more preferably from about 85:15 to about 97:3.

[0048] In general, the carboxymethylation reaction can be run at anytemperature at which the reactants and equipment can be convenientlyhandled. Typically, the reaction temperature will be within the range ofabout 50° C. to about 170° C., preferably is about 65° C. to about 140°C., more preferably is about 80° C. to about 130° C., and still morepreferably is about 95° C. to about 115° C.

[0049] The mole ratio of carbamoyl compound to carboxymethylationcatalyst metal atoms can vary over the range of about 0.1 to about 30.Preferably, it is about 0.5 to about 15, more preferably about 2 toabout 13.

[0050] Aldehydes useful in the process of the present invention may bepresent in pure form, in a polymeric form, in an aqueous solution, or asan acetal. A broad range of aldehydes can be used; the aldehyde maycontain more than one formyl group and, in addition to the oxygenatom(s) of the formyl group(s), the aldehyde may contain other oxygenatoms or other heteroatoms, such as in furfurylacetaldehyde,4-acetoxyphenylacetaldehyde, and 3-methylthiopropionaldehyde. Moresuitably, the aldehyde is of the general formula R—CHO wherein R ishydrogen, hydrocarbyl, or substituted hydrocarbyl. In general, Rcontains up to 20 carbon atoms, more suitably up to 10 carbon atoms.Examples of such aldehydes are phenylacetaldehyde, formylcyclohexane,and 4-methylbenzaldehyde. Preferably, R is hydrogen, a linear orbranched alkyl group containing up to 6 carbon atoms, or an arylalkylgroup where the aryl contains 6 to 12 carbon atoms and the alkylcontains up to 6 carbon atoms. More preferably, the aldehyde isformaldehyde, acetaldehyde, 3-methylthiopropionaldehyde orisobutyraldehyde, and in a particularly preferred embodiment, thealdehyde is formaldehyde with the source of the formaldehyde beingformalin.

[0051] In one embodiment of the present invention, an acid co-catalystis included in the reaction mixture. For some carbamoyl compounds, suchas acetamide (and acetamide equivalents), the acid co-catalyst ispreferably an organic acid, such as a carboxylic acid, having a pK_(a)greater than about 3. The organic acid co-catalyst can be, for example,formic acid, acetic acid, or propionic acid, preferably formic acid oracetic acid, and most preferably acetic acid. In general, when thecarbamoyl compound is an amide, it is preferred that the organic acidco-catalyst be the carboxylic acid which corresponds to the amide (i.e.,the carboxylic acid of which the amide is a derivative).

[0052] The carboxymethylation reaction can be run in the presence of asolvent which is chemically and physically compatible with the reactionmixture. Preferably, the solvent is a weaker base than the carbamoylcompound. The solvent can be, for example, an ether, a ketone, an ester,a nitrile, a carboxylic acid, a formamide such as dimethylformamide, ora mixture thereof. Preferably, the solvent is an ether, a ketone, or anitrile; more preferably, the solvent can be ethylene glycol,dimethoxyethane (DME), tetrahydrofuran (THF), acetone, 2-butanone,acetonitrile, acetic acid, or t-butyl methyl ether.

[0053] In a preferred embodiment, the carboxymethylation reaction iscarried out in the presence of water. In this embodiment, the molarratio of water to the carbamoyl compound in the carboxymethylationreaction mixture is generally less than about 10:1, preferably betweenabout 2:1 and about 5:1, and more preferably between about 3:1 and about4:1.

[0054] Payload is measured as the mass of carbamoyl compound divided bythe mass of reaction solvent. One skilled in the art will recognize thatuseful ranges of payload will depend in part on the physical state ofthe carbamoyl compound starting material under the reaction conditionsemployed and its compatibility with solvents used. The payload typicallywill vary through the range of about 0.001 grams of carbamoyl compoundper gram of solvent (g_(c)/g_(s)) in the reaction mixture to about 1g_(c)/g_(s). Preferably, it is at least about 0.01 g_(c)/g_(s), morepreferably at least about 0.1 g_(c)/g_(s), still more preferably betweenabout 0.12 g_(c)/g_(s) and about 0.35 g_(c)/g_(s)., and in aparticularly preferred embodiment, between about 0.15 g_(c)/g_(s) andabout 0.3 g_(c)/g_(s).

[0055] The reaction can be carried out in a batch mode or in acontinuous mode. When run in a continuous mode, the residence time inthe reaction zone can vary widely depending on the specific reactantsand conditions employed. Typically, residence time can vary over therange of about 1 minute to about 500 minutes, preferably about 10minutes to about 250 minutes, more preferably about 30 minutes to about100 minutes. When run in a batch mode, reaction time typically variesover the range of about 10 seconds to about 12 hours, preferably about 2minutes to about 6 hours, more preferably about 10 minutes to about 3hours.

C. Carboxymethylation Catalyst Recovery

[0056] After the carboxymethylation reaction, the catalyst is preferablyrecovered for reuse in a subsequent carboxymethylation reaction. Thenature of the recovery step will vary depending on the catalyst and anyrecovery method of the catalyst which is compatible with thecarboxymethylation reaction mixture and products can be used.

[0057] Weisenfeld (U.S. Pat. No. 4,954,466) reported a method ofrecovering cobalt catalyst values from carboxymethylation reactionmixtures wherein a cobalt-N-acetyliminodiacetic acid complex wasdissolved in an aqueous solution with a strong acid and then extractedwith a hydrocarbon solvent containing a trialkylamine to transfer thecobalt from the aqueous solution into the hydrocarbon solvent. Thecobalt was then stripped from the hydrocarbon solvent with water andprecipitated with a strong base.

[0058] Another method for the recovery of cobalt catalyst values fromcarboxymethylation reaction mixtures is described in European PatentApplication Publication No. EP 0 779 102 A1. In that method, cobalt isrecovered from carboxymethylation reaction mixtures such as thoseyielding N-acylsarcosines by treatment of the finished reaction mixturewith aqueous hydrogen peroxide or aqueous hydrogen peroxide and sulfuricacid, thereby converting the cobalt catalyst to water-soluble cobalt(II)salts. The aqueous phase containing the water-soluble cobalt(II) saltsis then separated from the nonaqueous phase. Excess hydrogen peroxide isnext removed from the aqueous phase, for example, by heating. An alkalimetal hydroxide is then added to the aqueous phase causing theprecipitation of cobalt(II) hydroxide. The cobalt(II) hydroxide is thencollected and washed in preparation for regeneration to cobalt catalyst.

[0059] Alternatively, and in accordance with one aspect of the presentinvention, cobalt from a completed carboxymethylation reaction mass isoxidized to a soluble cobalt(II) species. The oxidation step is carriedout by exposing the carboxymethylation reaction mixture upon completionto a molecular oxygen-containing gas for a suitable length of time. Theexposure to oxygen can be achieved by any convenient means, for example,by bubbling the oxygen-containing gas through the reaction mixture or bymaintaining an atmosphere of the oxygen-containing gas over the reactionmixture. The progress of the reaction can be monitored by color changesin which the final oxidized system is a deep red or red-purple colorwhich undergoes no further changes. Alternatively, the progress of thereaction can be monitored by infrared spectroscopy or by cyclicvoltametry.

[0060] The concentration of molecular oxygen in the oxygen-containinggas used in the cobalt recovery step of the present invention can varydepending on the reaction conditions. The concentration of oxygen istypically about 0.1% by weight to 100% by weight. Greater concentrationsof oxygen in the oxygen-containing gas will typically cause fasteroxidation reaction rates. However, relatively low concentrations ofoxygen in the oxygen-containing gas are favored when volatile organicsolvents are present in the reaction mixture, thereby presenting asafety risk. Preferably, the concentration of oxygen in theoxygen-containing gas is from about 5 wt. % to about 80 wt. %, morepreferably from about 10 wt. % to about 30 wt. %. The oxygen-containinggas can also contain a diluent gas. Preferably the diluent is inertunder the reaction conditions. Typical diluent gases are nitrogen,helium, neon, and argon, preferably nitrogen. Air can conveniently beused as the oxygen-containing gas. The oxidation can be carried outunder subatmospheric pressure, atmospheric pressure, or superatmosphericpressure. Preferably it is carried out at pressures ranging from about10 psi to about 100 psi (about 70 to about 700 kPa), more preferablyabout 30 to about 60 psi (about 200 to about 400 kPa).

[0061] The oxidized cobalt(II) species may be converted in situ into aninsoluble cobalt(II) salt complex with the N-acyl amino carboxylic acidreaction product by allowing the reaction mixture to stand for asuitable length of time. For example, it is convenient to allow thereaction mixture to stand overnight to achieve the precipitation of theinsoluble cobalt(II) salt complex. As the insoluble cobalt(II) saltcomplex forms, it precipitates out of solution.

[0062] Formation and precipitation of the insoluble cobalt(II) saltcomplex can be accelerated by raising the temperature of the system. Thetemperature of the reaction mixture during the oxidation step and duringthe complex-formation step of the present invention typically rangesfrom about room temperature to about 150° C., preferably from about 60°C. to about 110° C., more preferably from about 70° C. to about 100° C.

[0063] Alternatively, the formation and precipitation of the oxidizedcobalt(II) salts is facilitated by the presence of a composition such asan organic acid (for example, formic, acetic, oxalic, or propionic)which is present in the carboxymethylation step. Alternatively, thecomposition may be introduced upon completion of the carboxymethylationreaction step. The insoluble cobalt(II) salt complex can be separatedfrom the reaction mass by any convenient means, for example, byfiltration or centrifugation, and subsequently recycled to fresh cobaltcatalyst for use in additional carboxymethylation reaction. Theoxidation to the cobalt(II) species and conversion of the cobalt(II)species to an insoluble cobalt(II) salt complex can optionally beperformed as two discrete steps or combined into a single step in whichoxidation and salt formation are carried out in a nearly simultaneousfashion.

[0064] As a further alternative, the formation and precipitation of theoxidized cobalt(II) salts may also be accelerated by the addition of asolvent. Typical solvents include dimethylether (“DME”), acetone, or anysolvent suitable in the carboxymethylation step. In general, the amountof excess solvent is at least 50% of the volume of the reaction mass,more preferably about 75% to about 150% of the reaction mass, and mostpreferably between about 90% and about 110% of the reaction mass.

[0065] Instead of introducing molecular oxygen to the carboxymethylationreaction mixture, the cobalt(II) species may be formed under anaerobicconditions. In this approach, the reaction mixture is simply heated,refluxed or distilled at a temperature of about 60° C. to about 100° C.to effect the precipitation of an insoluble cobalt(II) salt. See, forinstance, Example 27. In addition, the formation and precipitation ofthe oxidized cobalt(II) salts may also be accelerated by the presence ofan organic acid or by the addition of a solvent as previously describedin the case when molecular oxygen is introduced to the system.

D. Catalyst Regeneration

[0066] Several methods for regenerating a cobalt catalyst have beenreported in the literature which may be used in accordance with oneaspect of the present invention. For example, in U.S. Pat. No. 4,954,466Weisenfeld suggests converting a cobalt(II) precipitate todicobaltoctacarbonyl by reacting the precipitate with carbon monoxideand hydrogen at a temperature of 150 to 180° C. with a pressure of 1500to 6000 psig (10,345 to 41,380 kPa).

[0067] Another method for regenerating a carboxymethylation cobaltcatalyst is described in European Patent Application Publication No. EP0 779 102 A1. In that method, cobalt hydroxide recovered from acarboxymethylation reaction is introduced into the melt of an N-acylamino acid derivative such as an N-acylsarcosine. The mixture is thenadded to a polar aprotic solvent and reacted with carbon monoxide or amixture of carbon monoxide and hydrogen to form a carboxymethylationcatalytic mixture.

[0068] Surprisingly, it has been discovered that the rate ofregeneration of the cobalt(II) salt can be dramatically increased if itis reacted with a carbamoyl compound of the present invention along withcarbon monoxide and hydrogen. Advantageously, the product of thisreaction is the base pair which participates in the carboxymethylationstep. When the carbamoyl compound is an amide, therefore, productivityis significantly increased by regenerating the cobalt(II) salt in thepresence of the amide. In addition, when the carbamoyl compound is aurea, the resulting base pair will react with carbon monoxide and analdehyde to produce an N-acyl amino carboxylic acid reaction product inrelatively good yield; a product which is not believed to have beenpreviously reported to have been obtained by a carboxymethylationreaction.

[0069] In accordance with the present invention, therefore, when thecarbamoyl compound is an amide the cobalt(II) salt can be regenerated inthe presence of the amide, an aldehyde, the amide and the aldehyde, orneither the amide or the aldehyde. When the carbamoyl compound is urea(or other compound which is a less competent base than the amides)however, the cobalt(II) salt is preferably regenerated in the presenceof the carbamoyl compound and in the essential absence of water andaldehyde sources which contain water. If the active catalyst mixture isregenerated in the absence of the carbamoyl compound, therefore, it isfurther advantageous to add the carbamoyl compound to the reactionmixture before the addition of the aldehyde source. For example, whenthe carbamoyl compound is a urea (structure (II) wherein R¹ is —NR³R⁴),it is advantageous to treat the cobalt(II) salt with carbon monoxide,hydrogen, and urea before the aldehyde source is added to the reactionmixture.

[0070] During regeneration, the reaction pressure generally ranges fromabout 200 psi to about 4,000 psi (1,400 to about 28,000 kPa), preferablyfrom about 800 psi to about 3,700 psi (5,600 to about 26,000 kPa), andmore preferably from about 1,500 psi to about 3,500 psi (10,500 to about24,000 kPa). In general, the carbon monoxide-to-hydrogen partialpressure ratio during regeneration ranges from about 99:1 to about 1:99,preferably from about 30:70 to about 90:10, and more preferably fromabout 50:50 to about 75:25. The progress of the regeneration reactioncan be followed by monitoring the uptake of gas, for example, bymonitoring head pressure. During the regeneration step it is oftenadvantageous to heat the reaction mixture. Typically, reaction mixturetemperatures range from about 70° C. to about 170° C., preferably fromabout 90° C. to about 150° C., and more preferably from about 100° C. toabout 140° C. Reaction times for the regeneration step can vary fromabout 1 minute to about 5 hours, preferably from about 5 minutes toabout 2 hours, and more preferably from about 10 minutes to about 1hour. If desired, the regeneration step can be performed in the presenceof the organic acid co-catalyst used in the carboxymethylation step. Theregenerated active catalyst complex can, if desired, be used in acarboxymethylation reaction directly after regeneration.

[0071] The anionic portion of the cobalt(II) salt is not critical to theregeneration step. For example, the cobalt(II) can be in the form of asalt of the conjugate base of the carboxymethylation reaction productfrom which the cobalt(II) was recovered. Alternatively, the cobalt(II)can be in any other convenient form such as cobalt acetate tetrahydrate,cobalt stearate, cobalt acetonate, or cobalt oxalate.

E. Deacylation

[0072] In many embodiments of the present invention, it is desired todeacylate the N-acyl amino carboxylic acid reaction product whichresults from the carboxymethylation step. In general, deacylation can beachieved by hydrolysis or by the formation of a diketopiperazinespecies.

[0073] In general, the N-acyl amino carboxylic acid reaction product ishydrolyzed in the presence of a hydrolysis catalyst, for example an acidor a base, preferably a mineral acid. Suitable mineral acids useful forthis purpose include hydrochloric acid, sulfuric acid, nitric acid,phosphoric acid, or phosphorous acid. Alternatively, the N-acyl reactionproduct may be hydrolyzed in the absence of a mineral acid to form anamino acid by heating the N-acyl amino carboxylic acid reaction productin the presence of water.

[0074] Instead of being hydrolyzed, the N-acyl amino carboxylic acidreaction product can be deacylated and cyclized in a single step to form2,5-diketopiperazines as depicted in Reaction Scheme 2:

[0075] wherein R² and R^(2a) are independently hydrogen, alkyl, orcarboxymethyl or the salts or esters thereof. Examples of such reactionsinclude the preparation of 1,4-di(carboxymethyl)-2,5-diketopiperazine(XVII) from N-acetyliminodiacetic acid (XVI) (see Reaction Scheme 7),the preparation of 2,5-diketopiperazine (XXX) from N-acetylglycine(XVIII) (see Reaction Scheme 9a), and the preparation of1,4-dimethyl-2,5-diketopiperazine (XXXI) from N-acetyl-N-methylglycine(XX) (See Reaction Schemes 11 and 15).

[0076] Typically, reaction temperatures for formation of thediketopiperazines ranges from about 100° C. to about 250° C., preferablyabout 150° C. to about 220° C., more preferably about 185° C. to about200° C. The reaction is relatively rapid, and reaction time typicallyranges from about 1 minute to about 10 hours, preferably about 5 minutesto about 5 hours, still more preferably about 10 minutes to about 3hours. The amount of added water measured as a percent of the startingmaterial generally ranges up to about 85 wt. %, preferably from about 5wt. % to about 70 wt. %, and more preferably from about 9 wt. % to about20 wt. %. If desired, a catalyst can be added to the reaction mixture.Preferably, it is an organic acid and still more preferably it is a C₁to about C₃ carboxylic acid. Most preferably, the acid catalyst isacetic acid. Solvents can optionally be present in the reaction mixture.For example, ethers, ketones, or nitrites can be added.

[0077] The formation of the 2,5-diketopiperazines from N-acyl amino acidreaction products is advantageous for a number of reasons. As a generalrule, they are less soluble in many solvents and in water than is thecorresponding amino acid. As a result, the diketopiperazine can be morereadily precipitated from the reaction mixture, separated, and handled.Furthermore, since the deacylation reaction does not require strongmineral acids, it is less corrosive to process equipment than ahydrolysis reaction in which strong mineral acids are employed.

[0078] The deacylation and hydrolysis reactions of N-acyl amino acidreaction products can occur simultaneously, resulting in a mixture ofproducts. This mixture of deacylation and hydrolysis products can besubsequently used as produced, i.e., without separation andpurification, or it can be separated into its component products.

[0079] The ratio of hydrolysis and deacylation products achieved in thefinal reaction mixture depends on the conditions selected for thereaction. For example, in Reaction Scheme 3, N-acetyliminodiacetic acid(XVI) is heated in water to form iminodiacetic acid (XIV),1,4-di(carboxymethyl)-2,5-diketopiperazine (XVII) or mixtures thereof.

[0080] The ratio of (XIV) to (XVII) can be controlled as a function ofthe various conditions under which the reaction is performed. Forexample, Table 1 demonstrates the effect upon the ratio of (XIV) to(XVII) as a consequence of heating N-acetyliminodiacetic acid (XVI) (45grams) under varying conditions of temperature, time, added water, andadded acetic acid. (See Example 28 for a more complete description).TABLE 1 Ratio Added Yield Yield of Temper- Added Acetic of of (XVII) Ex.ature Time water Acid (XVII) (XIV) to No. (° C.) (min) (g) (g) (g) (g)(XIV) 28.1 175 90 0 10 22.98 0.85 27.0 28.2 175 20 0 10 19.26 1.76 10.928.3 175 45 0  0 23.71 0.69 34.4 28.4 175 20 5 10 18.66 3.37  5.5 28.5195 45 0 10 23.98 0.36 66.6 28.6 195 45 5  0 24.78 0.29 85.4 28.7 195 455 10 23.74 0.83 28.6 28.8 195 20 5 10 23.15 0.92 25.2 28.9 195  5 5 1021.29 1.23 17.3

[0081] Reaction conditions can be selected, if desired, which maximizethe amount of compound (XVII) formed relative to the amount of compound(XIV) formed. By way of illustration, Examples 28.1 and 28.2 andExamples 28.7, 28.8 and 28.9 show that longer reaction times tend toincrease the ratio of (XVII) to (XIV). Similarly, Examples 28.4 and 28.8demonstrate that higher temperatures tend to increase the ratio of(XVII) to (XIV). In contrast, Examples 28.2 and 28.4 show thatincreasing the amount of added water decreases the ratio of (XVII) to(XIV). Examples 28.6 and 28.7 show that increasing the amount of addedcarboxylic acid, in this case, acetic acid, decreases the ratio of(XVII) to (XIV). At temperatures less than 100° C., the reaction canrequire several hours. By increasing pressure on the reaction system,temperatures well in excess of 100° C. can be achieved and under theseconditions hydrolysis and deacylation can be achieved in much shorterperiods of time, for example in minutes.

[0082] In general, a wide variety of N-acyl amino carboxylic acidreaction products useful in the present invention can be hydrolyzed ordeacylated using the conditions described herein. Examples of N-acylamino carboxylic acid reaction products which can be hydrolyzed ordeacylated and the products of the reactions as described herein are setforth in Table 2. TABLE 2 Examples of hydrolysis or deacylation productsN-acyl amino carboxylic acid reaction product Hydrolysis DeacylationStarting Material Product Product N,N,N′,N′- Iminodiacetic Nonetetra(carboxy- acid methyl)urea (XIV) (XIII) N-acetyl- Iminodiacetic1,4- iminodiacetic acid di(carboxymethyl)- acid (XVI) (XIV) 2,5-diketopiperazine (XVII) N-acetyl-N- N-(phosphono- 1,4- (phosphono-methyl)glycine di(phosphonomethyl)- methyl)glycine (I) 2,5- (XIX)diketopiperazine N,N′-di(carboxy- Sarcosine None methyl)-N,N′- (XXIII)dimethyl urea (XXII) N,N′-di(carboxy- N-(phosphono- None methyl)-N,N′-methyl)glycine di(phosphono- (I) methyl) urea (XXIV) N-acetyl-N-methylN-methylglycine 1,4-dimethyl-2, 5- glycine (XX) diketopiperazine (XXXI)N-acetylglycine Glycine 2,5-diketopiperazine (XVIII) (XXX)

F. Phosphonomethylation

[0083] In certain embodiments of the present invention it is preferredthat the N-acyl reaction product be phosphonomethylated.Phosphonomethylation reactions of amines and of amino acids have beenreported. For example, Moedritzer, et al. (J. Org. Chem. 1966, 31,1603-1607) reported the reaction of primary and secondary amino acidswith phosphorous acid and formaldehyde to form, respectively, di-andmono-phosphonomethylated amino acids. Moedritzer also reported (U.S.Pat. No. 3,288,846) the reaction of iminodiacetic acid (XIV) withphosphorous acid and formaldehyde to prepareN-(phosphonomethyl)-iminodiacetic acid (XV). Miller et al. (U.S. Pat.No. 4,657,705) disclose a process in which substituted ureas, amides andcarbamates are phosphonomethylated to produce an N-substitutedaminomethylphosphonic acid which can be converted to glyphosate; in thedisclosed process, the urea, amide or carbamate is (1) mixed with anaqueous acidic medium comprising phosphorous acid and an acid selectedfrom among sulfuric, hydrochloric and hydrobromic acids and (2) heatedto a temperature between about 70 and about 120° C. Phosphonomethylationreactions can also be carried out using phosphorous trichloride insteadof phosphorous acid (for example, U.S. Pat. No. 4,400,330).

[0084] Typically, the N-acyl amino carboxylic acid reaction product tobe phosphonomethylated is treated with a source of phosphorous acid anda source of formaldehyde. Another mineral acid such as sulfuric acid orhydrochloric acid is preferably added. Reaction temperatures generallyrange from about 80° C. to about 150° C., preferably from about 100° C.to about 140° C., more preferably from about 120° C. to about 140° C.Reaction times generally range from about 10 minutes to about 5 hours,preferably from about 20 minutes to about 3 hours, more preferably fromabout 30 minutes to about 2 hours. Any source of phosphorous acid orphosphorous acid equivalent can be used in the phosphonomethylationreaction. For example, phosphorous acid, phosphorous trichloride,phosphorous tribromide, phosphorous acid esters, chlorophosphonic acidand esters of chlorophosphonic acid can be used. Phosphorous acid andphosphorous trichloride are preferred. Formaldehyde can be derived fromany source, for example, paraformaldehyde or formalin.

[0085] In one embodiment of the present invention, thephosphonomethylation reaction results in the replacement of the N-acylsubstituent of the N-acyl amino carboxylic acid reaction product with anN-phosphonomethyl group to produce an N-(phosphonomethyl)amino acid.This reaction is shown generically in Scheme 4 wherein R¹ and R² are asdefined previously.

[0086] Examples of this type of reaction include the conversion ofN-acyl sarcosine to N-methyl-N-(phosphonomethyl)glycine,N-acyliminodiacetic acid to N-(phosphonomethyl)iminodiacetic acid, andN-acylglycine to glyphosate.

[0087] In another embodiment of the present invention,2,5-diketopiperazines are phosphonomethylated with phosphoroustrichloride, phosphorous acid, or a source of phosphorous acid in thepresence of a source of formaldehyde to formN-substituted-N-(phosphonomethyl)glycine as shown in Reaction Scheme 4a.

[0088] wherein R² and R^(2a) are independently hydrogen, alkyl, orcarboxymethyl or the salts or esters thereof.

[0089] In a further embodiment of the present invention, anN-acylglycine is phosphonomethylated to form N-(phosphonomethyl)glycine(I). For example, the reaction of N-acetylglycine (XVIII), phosphorousacid or phosphorous trichloride, and a source of formaldehyde producesN-(phosphonomethyl)glycine (I) (See Reaction Scheme 9).

[0090] In still further aspect of the present invention,N-acyl-N-alkylglycine compounds can be phosphonomethylated to produceN-alkyl-N-(phosphonomethyl)glycine compounds. For example,N-acetyl-N-methylglycine (XX) can be reacted with a source offormaldehyde and with phosphorous acid or phosphorous trichloride toproduce N-methyl-N-(phosphonomethyl)glycine (XXI) (See Reaction Schemes12 and 16).

G. Oxidative Dealkylation

[0091] In one embodiment of the present invention, thecarboxymethylation reaction product is converted toN-alkyl-N-(phosphonomethyl)glycine (“N-substituted glyphosate”) which isoxidatively dealkylated to generate N- (phosphonomethyl)glycine.Preferably, oxidation is carried out by combining the N-substitutedglyphosate with water and feeding the combination into a reactor alongwith an oxygen-containing gas or a liquid containing dissolved oxygen.In the presence of a noble metal catalyst, the N-substituted glyphosatereactant is oxidatively converted into glyphosate and variousbyproducts:

[0092] wherein R⁷, R⁸, and R⁹ are as previously defined, and R²¹ and R²²are independently hydrogen, halogen, —PO₃H₂, —SO₃H₂, —NO₂, hydrocarbylor unsubstituted hydrocarbyl other than —CO₂H.

[0093] In a preferred embodiment, the catalyst subsequently is separatedby filtration and the glyphosate then is isolated by precipitation, forexample, by evaporation of a portion of the water and cooling.

[0094] The amount of N-substituted glyphosate reactant in the aqueousmedium is typically from about 1 to about 80 wt. % ([mass ofN-substituted glyphosate reactant÷total reaction mass]×100%). Morepreferably, the amount of N-substituted glyphosate reactant is fromabout 5 to about 50 wt. %, and most preferably from about 20 to about 40wt. %.

[0095] Preferably, the reaction is conducted at a temperature of fromabout 50° C. to about 200° C. More preferably, the reaction is conductedat a temperature of from about 70° C. to about 150° C., and mostpreferably from about 125° C. to about 150° C.

[0096] The pressure in the reactor during the oxidation generallydepends on the temperature used. Preferably, the pressure is sufficientto prevent the reaction mixture from boiling. If an oxygen-containinggas is used as the oxygen source, the pressure also preferably isadequate to cause the oxygen to dissolve into the reaction mixture at arate sufficient to sustain the desired rate of reaction. The pressurepreferably is at least equal to atmospheric pressure. Preferably, thepressure is from about 30 to 200 psig. More preferably, when thetemperature is in the most preferred range of from about 125 to about150° C., the pressure is from about 40 to about 100 psig.

[0097] The oxygen source for the oxidation reaction may be anyoxygen-containing gas or a liquid containing dissolved oxygen.Preferably, the oxygen source is an oxygen-containing gas. As usedherein, an “oxygen-containing gas” is any gaseous mixture containingmolecular oxygen which optionally may contain one or more diluents whichare non-reactive with the oxygen or the reactant or product under thereaction conditions. Examples of such gases are air, pure molecularoxygen, or molecular oxygen diluted with helium, argon, neon, nitrogen,or other non-molecular oxygen-containing gases. Preferably, at leastabout 20% by volume of the oxygen-containing gas is molecular oxygen,and more preferably, at least about 50% of the oxygen-containing gas ismolecular oxygen.

[0098] The oxygen may be introduced by any conventional means into thereaction medium in a manner which maintains the dissolved oxygenconcentration in the reaction mixture at the desired level. If anoxygen-containing gas is used, it preferably is introduced into thereaction medium in a manner which maximizes the gas' contact with thereaction solution. Such contact may be obtained, for example, bydispersing the gas through a diffuser such as a porous glass frit or bysintering, shaking, or other methods known to those skilled in the art.

[0099] The oxygen preferably is fed to the reaction mixture at a ratewhich is sufficient to maintain the dissolved oxygen concentration at afinite level. More preferably, the oxygen is fed at a rate sufficient tomaintain the dissolved oxygen concentration at a value of no more thanabout 2 ppm, while sustaining the desired reaction rate. It should benoted that the partial pressure of the oxygen in the reactor affects therate at which oxygen is delivered to the reaction mixture and preferablyis from about 0.5 to about 10 atm.

[0100] The catalyst comprises a noble metal, preferably platinum (Pt),palladium (Pd), rhodium (Rh), iridium (Ir), osmium (Os), or gold (Au).In general, platinum and palladium are more preferred, and platinum ismost preferred. Because platinum is presently most preferred, much ofthe following discussion will be directed to use of platinum. It shouldbe understood, however, that the same discussion is generally applicableto the other noble metals and combinations thereof.

[0101] The noble metal catalyst may be unsupported, e.g., platinumblack, commercially available from various sources such as AldrichChemical Co., Inc., Milwaukee, Wis.; Engelhard Corp, Iselin, N.J.; andDegussa Corp., Ridgefield Park, N.J. Alternatively, the noble metalcatalyst may be deposited onto the surface of a support, such as carbon,alumina (Al₂O₃), silica (SiO₂), titania (TiO₂), zirconia (ZrO₂),siloxane, or barium sulfate (BaSO₄), preferably silica, titania, orbarium sulfate. Supported metals are common in the art and may becommercially obtained from various sources, e.g., 5% platinum onactivated carbon, Aldrich Catalogue No. 20,593-1; platinum on aluminapowder, Aldrich Catalogue No. 31,132-4; palladium on barium sulfate(reduced), Aldrich Catalogue No. 27,799-1; and 5% Palladium on activatedcarbon, Aldrich Catalogue No. 20,568-0. As to carbon supports, graphiticsupports generally are preferred because such supports tend to havegreater glyphosate selectivity.

[0102] The concentration of the noble metal catalyst on a support'ssurface may vary within wide limits. Preferably it is in the range offrom about 0.5 to about 20 wt. % ([mass of noble metal÷total mass ofcatalyst]×100%), more preferably from about 2.5 to about 10 wt. %, andmost preferably from about 3 to about 7.5 wt. %. At concentrationsgreater than about 20 wt. %, layers and clumps of noble metal tend toform. Thus, there are fewer surface noble metal atoms per total amountof noble metal used. This tends to reduce the catalyst's activity and isan uneconomical use of the costly noble metal.

[0103] The weight ratio of the noble metal to the N-substitutedglyphosate reactant in the reaction mixture preferably is from about1:500 to about 1:5. More preferably, the ratio is from about 1:200 toabout 1:10, and most preferably from about 1:50 to about 1:10.

[0104] In a preferred embodiment, a molecular electroactive molecule(i.e., a molecular species that may be reversibly oxidized or reduced byelectron transfer) is adsorbed to the noble metal catalyst. It has beendiscovered in accordance with this invention that selectivity and/orconversion of the noble metal catalyst may be improved by the presenceof the electroactive molecular species, particularly where the catalystis being used to effect the oxidation of NMG to form glyphosate. In thisinstance, the electroactive adsorbate preferably is hydrophobic and hasan oxidation potential (E_(½)) of at least about 0.3 volts vs. SCE(saturated calomel electrode). A compilation of the oxidation potentialand reversibility for a large number of electroactive species may befound in Encyclopedia of Electrochemistry of the Elements (A. Bard andH. Lund eds., Marcel Dekker, New York). Other references identifying theoxidation for specific electroactive species include: fortriphenylmethane, J. Perichon, M. Herlem, F. Bobilliart, and A.Thiebault Encyclopedia of Electrochemistry of the Elements vol. 11, p.163 (A. Bard and H. Lund eds., Marcel Dekker, New York, N.Y. 1978); forN-hydroxyphthalimide, Masui, M., Ueshima, T. Ozaki, S. J. Chem. Soc.Chem. Commun. 479-80 (1983); for tris(4-bromophenyl)amine, Dapperheld,S., Steckhan, E., Brinkhaus, K. Chem. Ber., 124, 2557-67 (1991); for2,2,6,6-tetramethylpiperdine-N-oxide (“TEMPO”), Semmelhack, M., Chou,C., and Cortes, D. J. Am. Chem. Soc., 105, 4492-4 (1983); for5,10,15,20-tetrakis (pentaf luorophenyl)-21H,23H-porphine iron(III)chloride (“Fe(III)TPFPP chloride”), Dolphin, D., Traylor, T., and Xie,L. Acc. Chem. Res., 30, 251-9 (1997); and for various porphyrins, J. H.Fuhrhop, Porphyrins and Metalloporphyrins 593 (K. Smith, ed., Elsevier,N.Y., 1975).

[0105] Electroactive molecular species also are useful in the context ofthe oxidation of N-isopropyl glyphosate to form glyphosate. In thatcontext, an electroactive molecular species preferably is adsorbed to anoble metal catalyst on a graphitic carbon support. In the presence ofthe graphitic carbon support, the electroactive molecular species hasbeen found to increase the noble metal catalyst's glyphosateselectivity.

[0106] Examples of generally suitable electroactive molecular speciesinclude triphenylmethane; N-hydroxyphthalimide; Fe(III)TPFPP chloride,2,4,7-trichlorofluorene; tris(4-bromophenyl)amine; 2,2,6,6-tetramethylpiperidine N-oxide (sometimes referred to as “TEMPO”);5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride (sometimesreferred to as “Fe(III)TPP chloride”); 5,10,15,20-tetraphenyl-21H,23Hporphine nickel(II) (sometimes referred to as (Ni(II) TPP”),4,-4′-difluorobenzophenone, and phenothiazine. When the noble metalcatalyst is being used to catalyze the oxidation of NMG to glyphosate,the most preferred electroactive molecular species includeN-hydroxyphthalimide; tris (4-bromophenyl) amine; TEMPO; Fe(III)TPPchloride; and Ni(II) TPP.

[0107] Electroactive molecular species may be adsorbed to the noblemetal catalyst using various methods generally known in the art. Theelectroactive molecular species may be added directly to the oxidationreaction mixture separately from the noble metal catalyst. For example,2,2,6,6-tetramethyl piperidine N-oxide (“TEMPO”) may be added to thereaction mixture without first being adsorbed to the noble metalcatalyst. Using this method, the electroactive molecule adsorbs to thenoble metal catalyst while in the reaction mixture. Alternatively, theelectroactive molecular species is adsorbed to the noble metal catalystbefore being added to the oxidation reaction mixture. Generally, theelectroactive molecular species may be adsorbed to the catalyst using,for example, liquid phase deposition or gas phase deposition.

[0108] The oxidation reaction preferably is carried out in a batchreactor so that the reaction may be contained until the conversion toglyphosate is complete. Other types of reactors, however, such ascontinuous stirred tank reactors may also be used, although preferably:(1) there should be sufficient contact between the oxygen, N-substitutedglyphosate reactant, and the catalyst; and (2) there should be adequateretention time for substantial conversion of the N-substitutedglyphosate reactant to glyphosate.

[0109] The oxidative cleavage can be performed, if desired, in thepresence of a solvent, for example, a water-containing solvent. It mayalso be performed in the presence of other chemical species, such asN-methyl glyphosate, aminomethylphosphonic acid (“AMPA”), andN-methyl-aminomethylphosphonic acid (“MAMPA”), which may arise inconnection with the preparation of glyphosate.

H. Preparation of Glyphosate

[0110] In a preferred embodiment of the present invention, the N-acylreaction product of the carboxymethylation reaction is converted toglyphosate or one of its salts or esters having the structure (I):

[0111] wherein R⁷, R⁸, and R⁹ independently comprise hydrogen,hydrocarbyl, substituted hydrocarbyl, or an agronomically acceptablecation. When R⁷, R⁸, and R⁹ of structure (I) are each hydrogen,structure (I) is glyphosate.

[0112] In general, the N-acyl reaction product may be converted toglyphosate when formaldehyde (or a formaldehyde source) is selected asthe aldehyde and the carbamoyl compound is selected from among thosecompounds having the structure (II):

[0113] wherein R¹ is hydrocarbyl, substituted hydrocarbyl, or —NR³R⁴, R²and R^(2a) are independently hydrogen, hydrocarbyl, or substitutedhydrocarbyl, provided that —NR²R^(2a) can be carboxymethylated.Preferably, formalin is selected as the formaldehyde source; R¹ is alkylor —NR³R⁴; R² and R³ are independently hydrogen, alkyl, hydroxymethyl,amidomethyl, phosphonomethyl, carboxymethyl, or an ester or salt ofcarboxymethyl or phosphonomethyl; and R^(2a) and R⁴ are independentlyhydrogen, hydroxymethyl or another substituent which is hydrolyzableunder the carboxymethylation reaction conditions. More preferably, R¹ ismethyl, ethyl, isopropyl, or —NR³R⁴; R² and R³ are independentlyhydrogen, methyl, ethyl, isopropyl, hydroxymethyl, carboxymethyl,phosphonomethyl or an ester or salt of carboxymethyl or phosphonomethyl;and R^(2a) and R⁴ are independently hydrogen or hydroxymethyl. Mostpreferably, R¹ is methyl or —NR³R⁴; R² and R³ are independentlyhydrogen, methyl, hydroxymethyl, carboxymethyl, phosphonomethyl, or anester or salt of carboxymethyl or phosphonomethyl; and R^(2a) and R⁴ areindependently hydrogen or hydroxymethyl. Exemplary carbamoyl compoundsthus include acetamide; urea; N-alkyl, N-phosphonomethyl, andN-carboxymethyl substituted acetamides; the esters and salts ofN-phosphonomethyl and N-carboxymethyl substituted acetamides;N,N′-dialkyl, N,N′-diphosphonomethyl, and N,N′-dicarboxymethylsubstituted ureas; the esters and salts of N,N′-diphosphonomethyl andN,N′-dicarboxymethyl substituted ureas; and amide equivalent compoundsselected from the group consisting of

[0114] wherein R¹³ and R¹⁴ are independently hydrogen, hydroxymethyl,alkyl, carboxymethyl, phosphonomethyl, or an ester or salt ofcarboxymethyl or phosphonomethyl; and R¹⁵, R¹⁶ and R¹⁷ are independentlyalkyl or —NR³R⁴. Preferred alkyl substituents for any of R¹³, R¹⁴, R¹⁵R¹⁶ and R¹⁷ are methyl, ethyl and isopropyl.

[0115] The sequence used to convert the N-acyl reaction product toglyphosate is dependent upon the starting carbamoyl compound. Ingeneral, however, the N-acyl group is hydrolyzed or otherwise removedfrom the N-acyl reaction product and, if the carbamoyl compound did notcontain an N-phosphonomethyl substituent, the reaction product isphosphonomethylated either simultaneously with or subsequent todeacylation to remove the N-acyl substituent. Additional steps which canbe employed include oxidative cleavage and carboxymethylation catalystrecycle, as described elsewhere herein.

Preparation of Glyphosate from Acetamide

[0116] The preparation of glyphosate using acetamide as the carbamoylcompound is depicted in Reaction Scheme 6.

[0117] As depicted, one equivalent of acetamide VII is reacted with twoequivalents each of carbon monoxide and formaldehyde in the presence ofa carboxymethylation catalyst precursor and solvent; under theseconditions the acetamide is protonated and forms a base pair (designatedas BH⁺[Co(CO)₄]⁻) with the carboxymethylation catalyst precursor. Thereaction produces N-acetyliminodiacetic acid XVI and acarboxymethylation catalyst reaction product (BH⁻[Co(CO)₄]⁻ wherein “B”is acetamide).

[0118] In the presence of water and an acid such as hydrochloric acid,N-acetyliminodiacetic acid XVI is hydrolyzed to form iminodiacetic acidXIV and acetic acid. The separated iminodiacetic acid XIV is reactedwith formaldehyde and H₃PO₃, PCl₃ or other H₃PO₃ source to produceN-(phosphonomethyl) iminodiacetic acid XV which is oxidized in thepresence of a carbon or platinum on carbon catalyst to yield glyphosateI.

[0119] The cobalt used in the carboxymethylation step of the reactioncan be recovered as a cobalt(II) salt as previously described in SectionC. In addition, regenerating the cobalt(II) salt in the presence ofacetamide (:B), carbon monoxide and hydrogen results in the formation ofthe base pair which is recycled to the carboxymethylation reactionmixture.

[0120] Similarly, the acetic acid which is generated by the hydrolysisof N-acetyliminodiacetic acid XVI to iminodiacetic acid XIV may bereacted with ammonia to form acetamide and recycled for use as astarting material in the carboxymethylation reaction. As a result, highatom efficiency is achieved by converting ammonia, carbon monoxide andformaldehyde into iminodiacetic acid.

[0121] In a preferred embodiment in which the amide is acetamide or anacetamide equivalent (that is, a composition which can be hydrolyzed toacetamide under the carboxymethylation reaction conditions), thereaction mixture for the carboxymethylation reaction contains aceticacid as an organic acid co-catalyst. Acetic acid, when used as aco-catalyst, has been found to provide the following surprising andsignificantly beneficial results:

[0122] 1) certain ratios of cobalt to acetic acid in thecarboxymethylation reaction mixture increases the yield of the N-acylamino carboxylic acid reaction product;

[0123] 2) the preferred ratio of cobalt to acetic acid exhibits apressure dependency;

[0124] 3) the presence of acetic acid results in an unexpected abilityto increase yield of the N-acyl amino carboxylic acid reaction productby increasing pressure (typically, increases in pressure will lead toincreased reaction rates but not yield); and

[0125] 4) the increase in yields which is attainable by increases inpressure allows for an increase in payload.

[0126] As a result, high yields of N-acetyliminodiacetic acid (XVI) canbe obtained at relatively high payloads.

[0127] In accordance with the present invention, the molar ratio ofacetic acid to cobalt is generally in the range of about 2 to about 60,preferably about 7 to about 55, and still more preferably about 10 toabout 50. At relatively lower pressures, for example, pressures lessthan about 1,800 psi (12,500 kPa), the molar ratio of acetic acid tocobalt is generally in the range of about 2 to about 20, preferablyabout 7 to about 15, and still more preferably about 11 to about 13. Atintermediate pressures, for example, pressures within the range of about1,800 to about 2,500 psi (12,500 to about 17,250 kPa), the molar ratioof acetic acid to cobalt is generally in the range of about 2 to about45, preferably about 8 to about 30, and still more preferably about 10to about 20. At relatively high pressures, for example, pressures of atleast about 2,500 psi (17,250 kPa), the molar ratio of acetic acid tocobalt is generally in the range of about 4 to about 60, preferablyabout 8 to about 55, and still more preferably about 10 to about 50. Thesurprising effect of using acetic acid on the carboxymethylation ofacetamide (VII), is illustrated in Example 22 and the table associatedtherewith which shows the percent yield of N-acetyliminodiacetic acid(XVI) based on starting amount of acetamide (VII) under differentreaction conditions of pressure, payload, solvent, added water, amountof Co₂(CO)₈ catalyst precursor, and added acetic acid co-catalyst.

[0128] The experimental data obtained to date further suggests thatyield is surprisingly improved when acetic acid is used as a co-catalystin the carboxymethylation of acetamide (VII) when water is present inthe reaction mixture. This effect is illustrated in the table whichappears in association with Example 23 which shows the percent yield ofN-acetyliminodiacetic acid (XVI) based on starting amount of acetamide(VII) when HOAc/Co ratio is varied against moles H₂O. Reactionconditions included 1500 psi CO:H₂ (95:5), 90 mL DME solvent, 11.8 gacetamide, 13.6 g of 95% paraformaldehyde, and 4.1 g Co₂(CO)₈.Typically, the molar ratio of water to acetamide starting material isabout 1 to about 5, preferably about 2 to about 4, and more preferablyabout 3.2 to about 3.8.

[0129] As illustrated in Example 24, the yield of N-acetyliminodiaceticacid surprisingly increases with increasing pressure. Conventionally,reaction rates, not yields increase with increasing pressure.Accordingly, if lesser catalyst loads or greater payloads are desiredfor the reaction mixture, it is preferred that the carboxymethylationreaction of acetamide be carried out at a pressure of at least about 500psi (3,500 kPa), more preferably at least about 1,500 psi (10,500 kPa),and most preferably about 3,000 to about 3,500 psi (21,000-24,000 kPa).

[0130] Example 25 further illustrates that an increase in pressureallows for an increase in payload. For a given catalyst load, increasingpressure permits an increase in payload while maintaining high,commercially acceptable yields of N-acetyliminodiacetic acid. Thus, forexample, increasing pressure from 1,500 psi (10,340 kPa) to 3,200 psi(22,000 kPa) allows the payload to be doubled without a loss in yield,whereas a doubling of payload at 1,500 psi (10,340 kPa) results in asignificant loss of yield.

[0131] An alternative route for the preparation of glyphosate I fromacetamide VII is illustrated in Reaction Scheme 7:

[0132] In general, the sequence of reactions in Reaction Scheme 7 is thesame as those in Reaction Scheme 6 except that N-acetyliminodiaceticacid XVI is deacylated to form1,4-di(carboxymethyl)-2,5-diketopiperazine XVII which is then directlyphosphonomethylated in the same manner as iminodiacetic acid XIV isphosphonomethylated in Reaction Scheme 6.

[0133] A third alternative reaction scheme for the preparation ofglyphosate I from acetamide VII is depicted in Reaction Scheme 8:

[0134] In general, the sequence of reactions in Reaction Scheme 8 is thesame as those in Reaction Scheme 7 except that1,4-di(carboxymethyl)-2,5-diketopiperazine XVII is hydrolyzed usingwater and an acid such as hydrochloric acid to iminodiacetic acid XIVwhich is then phosphonomethylated as described in Reaction Scheme 6.

[0135] A fourth alternative reaction scheme for the preparation ofglyphosate I from acetamide VII is depicted in Reaction Scheme 9:

[0136] As depicted in Reaction Scheme 9, one equivalent of acetamide VIIis reacted with one equivalent each of carbon monoxide and formaldehydein the presence of a carboxymethylation catalyst precursor and solventto yield N-acetylglycine XVIII. In this reaction sequence, the formationof the base pair, and recycle and regeneration of the cobalt(II) saltare as described in connection with Reaction Scheme 6.

[0137] In contrast to Reaction Scheme 6, however, N-acetylglycine XVIIIis reacted with formaldehyde and H₃PO₃, PCl₃ or other H₃PO₃ source toproduce N-(phosphonomethyl)-N-acetylglycine XIX which is hydrolyzedusing water and an acid such as hydrochloric acid to produce GlyphosateI and acetic acid. Acetic acid which is produced in the hydrolysis stepcan be reacted with ammonia to generate acetamide for thecarboxymethylation step.

[0138] A fifth alternative reaction scheme for the preparation ofglyphosate I from acetamide VII is depicted in Reaction Scheme 9a:

[0139] The sequence of reactions in Reaction Scheme 9a is comparable tothose set forth in Reaction Scheme 9 except that N-acetylglycine XVIIIis deacylated to form 2,5-diketopiperazine XXX. 2,5-diketopiperazine XXXis then reacted with formaldehyde and H₃PO₃, PCl₃ or other H₃PO₃ sourceto produce N-(phosphonomethyl)glycine I and acetic acid. Acetic acidwhich is produced in the hydrolysis step can be reacted with ammonia togenerate acetamide for the carboxymethylation step.

[0140] Instead of starting with acetamide in the forgoing reactionschemes, an acetamide equivalent may be used. As used herein, anacetamide equivalent is a composition which, upon hydrolysis, yieldsacetamide or hydroxymethyl acetamide. Examples of acetamide equivalentsinclude the following compositions:

[0141] Thus, for example, these compounds may be substituted foracetamide in any one of Reaction Schemes 6, 7, 8, 9 and 9a.

Preparation of Glyphosate from N-methylacetamide

[0142] The preparation of N-(phosphonomethyl)glycine using N-methylaceatamide as the carbamoyl compound is depicted in Reaction Scheme 10:

[0143] As depicted, one equivalent of N-methylacetamide IX is reactedwith one equivalent each of carbon monoxide and formaldehyde in thepresence of a carboxymethylation catalyst precursor and solvent to yieldN-acetylsarcosine XX. In the presence of water and an acid such ashydrochloric acid, N-acetylsarcosine XX is hydrolyzed to sarcosine XXIIIand acetic acid. Sarcosine XXIII is reacted with formaldehyde and H₃PO₃,PCl₃ or other H₃PO₃ source to produceN-(phosphonomethyl)-N-methyl-glycine XXI which is oxidized in thepresence of a platinum catalyst and oxygen to glyphosate I.

[0144] Similar to the preparation of glyphosate from acetamide asdescribed in connection with Reaction Scheme 6, the carboxymethylationcatalyst reaction product (BH⁺[Co(CO)₄]⁻ wherein “B” isN-methylacetamide) is recycled and then regenerated in the presence ofN-methylacetamide.

[0145] Also, acetic acid which is generated by the hydrolysis ofN-acetylsarcosine XX to sarcosine XXIII is reacted with methylamine toform N-methylacetamide and recycled for use as a starting material inthe carboxymethylation reaction.

[0146] An alternative route for the preparation of glyphosate I fromN-methylacetamide IX is illustrated in Reaction Scheme 11:

[0147] In general, the sequence of reactions in Reaction Scheme 11 isthe same as those in Reaction Scheme 10 except that N-acetylsarcosine XXis deacylated to form 1,4-dimethyl-2,5-diketopiperazine XXXI.1,4-dimethyl-2,5-diketopiperazine XXXI is then directlyphosphonomethylated in the same manner as sarcosine XXIII isphosphonomethylated in Reaction Scheme 10. Alternatively,1,4-dimethyl-2,5-diketopiperazine XXXI is hydrolyzed to sarcosine XXIIIand phosphonomethylated as described in connection with Reaction Scheme10.

[0148] A third alternative reaction scheme for the preparation ofglyphosate I from N-methylacetamide IX is depicted in Reaction Scheme12:

[0149] As depicted, the carboxymethylation step of Reaction Scheme 12 isthe same as the carboxymethylation step of Reaction Schemes 10 and 11.In Reaction Scheme 12, however, N-acetylsarcosine XX is reacted withformaldehyde and H₃PO₃, PCl₃ or other H₃PO₃ source to produceN-(phosphonomethyl)-N-methyl-glycine XXI which is oxidized in thepresence of a platinum catalyst and oxygen to Glyphosate I and aceticacid. The acetic acid is then reacted with methylamine to yield theN-methylacetamide starting material.

Preparation of Glyphosate from N-acetglycine XVIII

[0150] The preparation of N-(phosphonomethyl)glycine starting fromN-acetglycine XVIII is depicted in Reaction Schemes 13 and 14. In thisReaction Scheme, N-acetglycine XVIII is carboxymethylated to yieldN-acetyliminodiacetic acid XVI which is then converted to Glyphosate Ias described in Reaction Schemes 6, 7, and 8.

[0151] Acetic acid is produced as a hydrolysis product in each ofReaction Schemes 13 and 14. The acetic acid is reacted with ammonia togenerate acetamide VII which can then be carboxymethylated to makecompound XVIII.

Preparation of Glyphosate from N-methylacetamide Equivalent

[0152] The preparation of N-(phosphonomethyl)glycine using VIII which isan N-methylacetamide equivalent is depicted in Reaction Schemes 15 and16. Thus, VIII is carboxymethylated to form N-methyl-N-acetylglycine XXwhich is converted to Glyphosate I as described in Reaction Schemes 10,11 and 12.

Preparation of Glyphosate from Urea

[0153] The preparation of N-phosphonomethyl)glycine from urea isdepicted in Reaction Scheme 17:

[0154] As depicted, one equivalent of urea V is reacted with fourequivalents each of carbon monoxide and formaldehyde in the presence ofa carboxymethylation catalyst precursor and solvent. In contrast toReaction Scheme 6, in this Reaction Scheme urea V is reacted with thecarboxymethylation catalyst precursor in the absence of formalin to formthe base pair (BH⁺[Co(CO)₄]⁻ wherein B is urea). The products of thecarboxymethylation reaction are the tetraacid XIII and thecarboxymethylation catalyst reaction product (BH⁺[Co(CO)₄]⁻ wherein “B”is urea). Tetraacid XIII is hydrolyzed to 2 equivalents of iminodiaceticacid XIV and carbon dioxide and iminodiacetic acid XIV is converted toGlyphosate I as described in connection with Reaction Schemes 6 and 8.

Preparation of Glyphosate from N,N-dimethylUrea

[0155] The preparation of N-(phosphonomethyl)glycine fromN,N-dimethylurea is depicted in Reaction Scheme 18:

[0156] As depicted, one equivalent of N,N-dimethylurea X is reacted withtwo equivalents each of carbon monoxide and formaldehyde in the presenceof a carboxymethylation catalyst precursor and solvent. Similar toReaction Scheme 18, in this reaction scheme N,N-dimethylurea X isreacted with the carboxymethylation catalyst precursor in the absence offormalin to form the base pair (BH⁺[Co(CO)₄]⁻) wherein BH⁺ is theprotonated N,N′-dimethylurea X.

[0157] The products of the carboxymethylation reaction are the diacidXXII and the carboxymethylation catalyst reaction product (BH⁺[Co(CO)₄]⁺wherein B is N,N′-dimethylurea). Diacid XXII is hydrolyzed to 2equivalents of sarcosine XXIII and carbon dioxide and sarcosine XXIII isconverted to Glyphosate I as described in connection with ReactionSchemes 10 and 15.

[0158] An alternative method for the preparation of N-(phosphonomethyl)glycine I from N,N′-dimethylurea X is depicted in Reaction Scheme 19:

[0159] As depicted, the carboxymethylation reaction is carried out asdescribed in connection with Reaction Scheme 18 to yield diacid XXII andthe carboxymethylation catalyst reaction product (BH⁺[Co(CO)₄]⁻ wherein“B” is N,N′-dimethylurea). In this reaction scheme, however, diacid XXIIis reacted with formaldehyde and H₃PO₃, PCl₃ or other H₃PO₃ source toproduce N-(phosphonomethyl)-N-methyl-glycine XXI which is oxidized inthe presence of a platinum catalyst and oxygen to glyphosate I.

Preparation of Glyphosate from bis-phosphonomethylurea

[0160] The preparation of N-(phosphonomethyl)glycine frombis-phosphonomethylurea XII is depicted in Reaction Scheme 20:

[0161] As depicted, one equivalent of bis-phosphonomethylurea XII isreacted with two equivalents each of carbon monoxide and formaldehyde inthe presence of a carboxymethylation catalyst precursor and solvent. Inthis reaction scheme bis-phosphonomethylurea XII is reacted with thecarboxymethylation catalyst precursor in the absence of formalin to formthe base pair (BH⁺[Co(CO)₄]⁻) wherein BH⁺ is the protonatedbis-phosphonomethylurea XII.

[0162] The products of the carboxymethylation reaction are XXIV and thecarboxymethylation catalyst reaction product (BH⁺[Co(CO)₄]⁻ wherein “B”is bisphosphonomethylurea). XXIV is hydrolyzed in the presence of ahydrolysis catalyst (preferably an acid or base, and more preferably amineral acid) to form N-(phosphonomethyl) glycine I.

Preparation of Glyphosate from N-acetyl-N-phosphonomethylamine

[0163] The preparation of N-(phosphonomethyl)glycine I fromN-acetyl-N-phosphonomethylamine XI is depicted in Reaction Scheme 21:

[0164] As depicted, one equivalent of N-acetyl-N-phosphonomethylamine XIis reacted with one equivalent each of carbon monoxide and formaldehydein the presence of a carboxymethylation catalyst precursor and solvent.In this reaction scheme N-acetyl-N-phosphonomethylamine is reacted withthe carboxymethylation catalyst precursor in the absence of formalin toform the base pair (BH⁺[Co(CO)₄]⁻) wherein BH⁺ is the protonatedN-acetyl-N-phosphonomethylglycine XI.

[0165] The products of the carboxymethylation reaction are XIX and thecarboxymethylation catalyst reaction product (BH⁺[Co(CO)₄]⁻ wherein “B”is N-acetyl-N-phosphonomethylamine). XIX is hydrolyzed in the presenceof a hydrolysis catalyst (preferably an acid or base, and morepreferably a mineral acid) to form N-(phosphonomethyl) glycine I.

Definitions

[0166] The following definitions are provided in order to aid the readerin understanding the detailed description of the present invention:

[0167] “Glyphosate” means N-(phosphonomethyl)glycine in acid form or anyof its salt or ester forms.

[0168] “Hydrocarbyl” means a group composed of carbon and hydrogen. Thisdefinition includes alkyl, alkenyl, and alkynyl groups which are eachstraight chain, branched chain, or cyclic hydrocarbons from one to abouttwenty carbons. Also included in this definition are aryl groupscomposed of carbon and hydrogen. Hydrocarbyl therefore includes, forexample, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, ethenyl,propenyl, butenyl, pentenyl, hexenyl, ethyne, propyne, butyne, pentyne,hexyne, phenyl, naphthyl, anthracenyl, benzyl, and isomers thereof.

[0169] “Substituted hydrocarbyl” means a hydrocarbyl group in which oneor more hydrogen has been substituted with a heteroatom-containinggroup. Such substituent groups include, for example, halo, oxo,heterocycle, alkoxy, hydroxy, aryloxy, —NO₂, amino, alkylamino, oramido. When the substituent group is oxo, the substituted hydrocarbylcan be, for example, an acyl group.

[0170] “Heteroatom” means an atom of any element other than carbon orhydrogen which is capable of forming chemical bonds.

[0171] “Heterocycle” means a saturated or unsaturated mono- ormulti-ring carbocycle wherein one or more carbon atoms is replaced by N,S, P, or O. This includes, for example, the following structures:

[0172] wherein Z, Z′, Z″, or Z′″ is C, S, P, O, or N, with the provisothat one of Z, Z′, Z″, or Z′″ is other than carbon, but is not O or Swhen attached to another Z atom by a double bond or when attached toanother O or S atom. Furthermore, the optional substituents areunderstood to be attached to Z, Z′, Z″, or Z′″ only when each is C. Thepoint of attachment to the molecule of interest can be at the heteroatomor elsewhere within the ring.

[0173] “Halogen” or “halo” means a fluoro, chloro, bromo, or iodo group.

[0174] “Carbamoyl” means a group containing a fully saturated nitrogenatom attached by a single bond to a carbonyl moiety.

[0175] “Carboxymethyl” means a group containing a carboxylate moietyattached by the carboxylate carbon atom to a saturated carbon atom whichin turn is attached to the molecule of interest.

[0176] “Carboxymethylation catalyst” means a catalyst which is useful incarbonylation reactions, and particularly in carboxymethylationreactions.

[0177] “Carboxymethylation” means the introduction of a substituted orunsubstituted carboxymethyl group into the molecule of interest.

[0178] “Payload” means the mass of starting material divided by the massof reaction solvent.

[0179] “PM” means phosphonomethylation.

[0180] “GC” means gas chromatography.

[0181] “HPLC” means high pressure liquid chromatography.

[0182] “IC” means ion chromatography.

[0183] “NMR” means nuclear magnetic resonance spectroscopy.

[0184] “MS” means mass spectrometry.

[0185] The following examples will illustrate the invention.

EXAMPLES

[0186] In the representative examples below of carboxymethylation,either a 300 or 2000 mL stainless steel autoclave equipped with amagnetic stirrer and heating system was employed. All compound numbersare in Roman numerals and reflect the structures which appear inReaction Schemes 1-21. The progress of the reaction was monitored byfollowing the consumption of gas. At the end of each heating period thereaction mixture was cooled to ambient temperature before analysis.N-Acetyliminodiacetic acid (XVI) was quantified by HPLC analysisutilizing an Interaction Ion 310 ion exclusion column at 30° C. and UVabsorption detection at 210 nm. The 0.04 N H₂SO₄ mobile phase pumped at0.5 mL/min. gave retention times from 4.6-4.8 min. for (XVI). All yieldsare based on moles of acetamide charged.

Example 1

[0187] Example 1 and 2 illustrate that increasing the reaction pressurehas no effect on yield of (XVI) when using HCl as a co-catalyst.

[0188] A 300 mL autoclave was charged with acetamide (VII) (11.8 g, 0.2mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72mole), 37% HCl (1.8 g, 0.018 mole), DME (90 mL), and Co₂(CO)₈ (4.1 g,0.012 mole) and pressurized to 1500 psi (10,345 kPa) CO at 25° C. Thismixture was heated to 110° C. for 30 minutes. HPLC analysis of thisstream gave an 87% yield of (XVI), 0.5% iminodiacetic acid (XIV) and4.0% N-acetylglycine (XVIII).

Example 2

[0189] A 300 mL autoclave was charged with acetamide (VII) (11.8 g, 0.2mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72mole), 37% HCl (1.8 g, 0.018 mole), DME (90 mL), and Co₂(CO)₈ (4.1 g,0.012 mole) and pressurized to 4000 psi (27,580 kPa) CO at 25° C. Thismixture was heated to 110° C. for 30 min. HPLC analysis of this streamgave an 87% yield of (XVI), 0.5% (XIV), and 4.0% (XVIII).

Example 3

[0190] This example illustrates a typical reaction in the absence ofadded acetic acid.

[0191] A 300 mL autoclave was charged with acetamide (VII) (11.8 g, 0.2mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72mole), DME (90 mL), and Co₂ (CO)₈ (4.1 g, 0.012 mole) and pressurized to1500 psi (10,345 kPa) CO:H₂ (95:5) at 25° C. for 30 min. HPLC analysisof this stream gave an 89% yield of (XVI), 1% (XIV), and 8% (XVIII).

Example 4

[0192] This example illustrates the unexpected increase in yield of(XVI) observed when a specific mole ratio of acetic acid to cobaltcatalyst is maintained at 1500 psi (10,345 kPa). A typical reaction isdescribed below. Summarized in Table 1 and FIG. 1 are the results ofreactions run under identical conditions as described below but withvarying amounts of added acetic acid. An autoclave was charged withacetamide (VII) (11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43mole), water (12.9 g, 0.72 mole), acetic acid (5.4 g, 0.09 mole),dimethoxyethane (DME) (90 mL), and Co₂ (CO)₈ (4.1 g, 0.012 mole) andpressurized to 1500 psi (10,345 kPa) CO:H₂ (95:5) at 25° C. This mixturewas heated to 125° C. for 30 min. The reaction was allowed to cool toroom temperature. HPLC analysis of the reaction gave a 92% yield of(XVI), 1% (XIV), and 7% (XVIII). TABLE 3 Yield vs. added acetic acid at1500 psi (10,345 kPa) Mole Ratio Acetic Acetic Acid Cobalt Acetic %Yield acid (g) (moles) (moles)^(b) acid/Co (XVI) 0^(a) 0 0.024 — 89  5.40.09 0.024 3.7 92 10.6 0.17 0.024 7.0 92 16.8 0.28 0.024 11.6 93 18.00.30 0.024 12.5 98 21.6 0.36 0.024 15.0 81

Example 5

[0193] This example illustrates that the optimal mole ratio of aceticacid to cobalt needed to achieve high yields of (XVI) varies withreaction pressure. A typical reaction is described below where thereaction was conducted at 3200 psi (22,069 kPa). Summarized in Table 4and FIG. 2 are the results of reactions run under identical conditionsas described below but with various amounts of added acetic acid.

[0194] An autoclave was charged with acetamide (VII) (11.8 g, 0.2 mole),95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72 mole),acetic acid (4.2 g, 0.07 mole), tetrahydrofuran (THF) (90 mL), andCo₂(CO)₈ (1 g, 0.003 mole) and pressurized to 3200 psi (22,069 kPa)CO:H₂ (95:5) at 25° C. This mixture was heated to 125° C. for 30 min.The reaction was allowed to cool to room temperature. HPLC analysis ofthe reaction gave 97% yield of (XVI). TABLE 4 Yield vs. added aceticacid at 3200 psi Mole Ratio Acetic Acetic Acid Cobalt Acetic % Yieldacid (g) (moles) (moles)^(b) acid/Co (XVI) 0^(a) 0 0.006 — 89 2.1 0.0350.006 5.8 88 3.1 0.051 0.006 8.5 87 4.2 0.07 0.006 11.6 97 16.8  0.280.006 46.6 96

Example 6

[0195] This example illustrates that the optimum acetic acid:cobalt moleratio varies with reaction pressure.

[0196] A 300 mL autoclave was charged with acetamide (VII) (11.8 g, 0.2mole), 95% paraformaldehyde (13.6 g, 0.42 mole), water (12.9 g, 0.72mole), acetic acid (21.2 g, 0.33 mole, 0.24 g/mL of DME), DME (90 mL),and Co₂ (CO)₈ (4.1 g, 0.012 mole) and pressurized to 2200 psi (15,170kPa) CO:H₂ (95:5) at 25° C. This mixture was heated to 125° C. for 30min. HPLC analysis of this stream gave a 95% yield of (XVI), 1% (XIV),and 3% (XVIII).

Example 7

[0197] This example illustrates the production of extremely high yieldsof (XVI) utilizing the process of this invention.

[0198] A 300 mL autoclave was charged with acetamide (5.9 g, 0.1 mole),95% paraformaldehyde (6.8 g, 0.22 mole), water (6.45 g, 0.36 mole),acetic acid (10.6 g, 0.18 mole, 0.12 g/mL of DME), DME (90 mL), andCo₂(CO)₈ (2.0 g, 0.0058 mole) and pressurized to 1500 psi (10,345 kPa)CO:H₂ (95:5) at 25° C. This mixture was heated to 125° C. for 30 min.HPLC analysis of the reaction gave a 99% yield of (XVI) and 1% (XVIII).

Example 8

[0199] This example illustrates the preparation of (XVI) in the presenceof reduced levels of cobalt catalyst.

[0200] An autoclave was charged with acetamide (VII) (11.8 g, 0.2 mole),95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72 mole),acetic acid (16.8 g, 0.28 mole, 0.19 g/mL of DME), DME (90 mL), andCo₂(CO)₈ (2.1 g, 0.006 mole) and pressurized to 2500 psi (17,240 kPa)CO:H₂ (95:5) at 25° C. This mixture was heated to 125° C. for 30 min.HPLC analysis of this stream gave a 97% yield of (XVI), 1% (XIV), and0.5% (XVIII).

Example 9

[0201] This example illustrates one way in which a cobalt(II) salt canbe recovered for recycle from the carboxy- methylation reaction mixture.

[0202] A distillation apparatus was charged with a (XVI) reaction streamrepresented by Example 2. Once the bottoms temperature of 90° C. wasmaintained, a distillate with a vapor temperature of 85° C. wascollected in a receiving flask. At this time, anhydrous DME was added tothe distillation pot at a rate similar to the removal of the 85° C.distillate. After removal of 115 g of 85° C. distillate and addition of120 g DME, a pink precipitate Co(N-acetyliminodiacetic acid)₂ waspresent in the distillation pot. This solid was isolated by filtration.Analysis of the filtrate revealed that it contained 13 ppm cobalt,implying that 99.8% of the cobalt was removed from the reaction stream.

Example 10

[0203] This example illustrates how a catalyst precursor can beregenerated from a cobalt(II) salt and used in the reaction step to givehigh yields of (XVI).

[0204] An autoclave was charged with cobalt acetate tetrahydrate (26.85g, 0.108 mole) and acetic acid (106 g, 1.77 mole) and pressurized to2200 psi (15,170 kPa) CO:H₂ (90:10) at 25° C. This mixture was heated to130° C. for 5 h. Gas uptake indicated that approximately 55% of thecobalt(II) salt had been converted to catalyst precursor.

[0205] The regenerated catalyst precursor was transferred, under CO:H₂pressure, into the autoclave containing CO:H₂ (95:5) at 800 psi (5517kPa), acetamide (VII) (29.5 g, 0.5 mole), 95% paraformaldehyde (34.0 g,1.08 mole), water (32.2 g, 1.79 mole), and DME (650 mL). A CO:H₂ (95:5)atmosphere at 1500 psi (10,345 kPa) was immediately established. Thismixture was heated to 100° C. The reaction warmed to 125° C. and wasmaintained at this temperature for one hour. HPLC analysis of thisstream gave a 95% yield of (XVI), 2% (XIV), 2.5% (XVIII), and 0.5%N-methyliminodiacetic acid.

Example 11

[0206] This example illustrates how a cobalt(II) salt can be regeneratedand used in the reaction step to give (XVI).

[0207] An autoclave was charged with cobalt acetate tetrahydrate (40.0g, 0.158 mole), Co₂(CO)₈ (4.1 g, 0.012 mole) and acetic acid (102 g,1.70 mole) and pressurized to 2200 psi (15,170 kPa) CO:H₂ (90:10) at 25°C. This mixture was heated to 130° C. for one hour. Gas uptake indicatedthat approximately 55% of the cobalt(II) salt had been converted tocatalyst precursor.

[0208] The regenerated catalyst precursor was transferred under CO:H₂pressure, into the autoclave at 95° C. containing CO:H₂ (95:5) at 900psi (6,210 kPa), acetamide (VII) (59.0 g, 1.0 mole), 95%paraformaldehyde (68.0 g, 2,16 mole), water (64.5 g, 3.60 mole) and DME(750 mL). A CO:H₂ atmosphere (95:5) at 1500 psi (10,345 kPa) wasimmediately established. This mixture was heated to 125° C. and wasmaintained at this temperature for one hour. HPLC analysis of thisstream gave a 77% yield of (XVI), 4% (XIV), 7.0% (XVIII), and 0.1%N-methyliminodiacetic acid.

Example 12

[0209] This example illustrates how a cobalt(II) salt can be regeneratedand used in the reaction step to give high yields of (XVI).

[0210] An autoclave was charged with cobalt acetate tetrahydrate (40.0g, 0.158 mole), Co₂(CO)₈ (4.1 g, 0.012 mole) and acetic acid (100 g,1.69 mole) and pressurized to 2200 psi (15,170 kPa) CO:H₂ (90:10) at 25°C. This mixture was heated to 130° C. for one hour. Gas uptake indicatedthat approximately 51% of the cobalt(II) salt had been converted tocatalyst precursor.

[0211] The regenerated catalyst precursor was transferred under CO:H₂pressure, into the autoclave at 95° C. containing CO:H₂ (95:5) at 900psi (6,210 kPa), acetamide (VII) (59.0 g, 1.0 mole), 95%paraformaldehyde (68.0 g, 2,16 mole), water (64.5 g, 3.60 mole) and DME(600 mL). A CO:H₂ atmosphere (95:5) at 2200 psi (15,170 kPa) wasimmediately established. This mixture was heated to 125° C. and wasmaintained at this temperature for one hour. HPLC analysis of thisstream gave a 95% yield of (XVI), 4% (XIV), 7.0% (XVIII), and 0.1%N-methyliminodiacetic acid.

Example 13

[0212] This example illustrates the advantage of conducting theregeneration of a Co(II) salt to an active carboxy- methylation catalystin the presence of an amide.

[0213] A 2 L autoclave was charged with acetamide (VII) (128.5 g, 2.2mole), Co(OAc)₂.4H₂O (33 g, 0.13 mole), THF (750 mL), and acetic acid(250 mL). After sealing the autoclave, 2200 psi (15,172 kPa) of CO:H₂(70:30) was established at 25° C. with stirring at 2000 rpm. Thecontents of the autoclave were heated to 130° C. and 3200 psi (22,069kPa) CO:H₂ (70:30) was established. After approximately 10 min., rapidgas uptake was observed indicative of the regeneration of the cobalt(II)salt.

[0214] For comparison purposes, this procedure was repeated four timesexcept that in one, a 90:10 CO:H₂ partial pressure ratio was used in theabsence of acetimide and in 1,000 mL acetic acid (no THF) to yield (topbar), 960 ml THF and 40 mL acetic acid (second bar down); third, no THF,no acetimide; fourth bar down, no THF. The advantage of having addedamide during the regeneration is further illustrated in FIG. 3, whichshows the tremendous increase in the rate of regeneration that isachieved in the presence of added amide compared to examples where noamide is added.

Example 14

[0215] This example illustrates the conversion of a variety of differentcobalt(II) salts to an active carboxymethylation catalyst mixture in thepresence of added amide.

[0216] A) A 2 L autoclave was charged with acetamide (VII)(128.5 g, 2.2mole), Co(II) stearate (83 g, 0.13 mole), and acetic acid (1 L). Aftersealing the autoclave, 2200 psi (15,172 kPa) of CO:H₂ (70:30) wasestablished at 25° C. with stirring at 2000 rpm. The contents of theautoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H₂ (70:30)was established. After approximately 10 min., rapid gas uptake wasobserved.

[0217] B) A 2 L autoclave was charged with acetamide (VII)(128.5 g, 2.2mole), cobalt(II) acetylacetonate (34 g, 0.13 mole), and acetic acid (1L). After sealing the autoclave, 2200 psi (15,172 kPa) of CO:H₂ (70:30)was established at 25° C. with stirring at 2000 rpm. The contents of theautoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H₂ (70:30)was established. After approximately 17 min., rapid gas uptake wasobserved.

[0218] C) A 2 L autoclave was charged with acetamide (VII)(128.5 g, 2.2mole), cobalt(II) bis-N-acetyliminodiacetate (48.4 g, 0.12 mole), andacetic acid (1 L). After sealing the autoclave, 2200 psi (15,172 kPa) ofCO:H₂ (70:30) was established at 25° C. with stirring at 2000 rpm. Thecontents of the autoclave were heated to 130° C. and 3200 psi (22,069kPa) CO:H₂ (70:30) was established. After approximately 20 min., rapidgas uptake was observed.

Example 15

[0219] These examples illustrate how different amides can be used in theprocess of this invention.

[0220] A) A 2 L autoclave was charged with urea (V) (60 g, 1.0 mole),Co(OAc)₂.4H₂O (66 g, 0.26 mole), and acetic acid (1 L). After sealingthe autoclave, 2200 psi (15,172 kPa) of CO:H₂ (70:30) was established at25° C. with stirring at 2000 rpm. The contents of the autoclave wereheated to 130° C. and 3200 psi (22,069 kPa) CO:H₂ (70:30) wasestablished. After approximately one hour, rapid gas uptake wasobserved. The reaction mass was cooled to 85° C. and the feed gas waschanged to a CO:H₂ (90:10) composition. Under a constant 3200 psi(22,069 kPa), 47 Wt. % formalin (320 mL, 5.28 mole) was delivered at 16mL/min. The reaction was stirred at 85° C. for 90 min. after theformalin addition was complete. Then the reaction was cooled to 25° C.,removed from the autoclave, and concentrated to an oil under reducedpressure. The oil was treated with 2 L of 10% HCl at 100° C. for twohours. This resulted in a 13% yield of (XIV) and 5% glycine.

[0221] B) A 2 L autoclave was charged with methylene bisacetamide (VI)(130 g, 1.0 mole), Co(OAc)₂.4H₂O (49 g, 0.20 mole), and THF (1 L). Aftersealing the autoclave, 2200 psi (15,172 kPa) of CO:H₂ (70:30) wasestablished at 25° C. with stirring at 2000 rpm. The contents of theautoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H₂ (70:30)was established. After approximately 0.5 h, rapid gas uptake wasobserved. Under a constant 3200 psi (22,069 kPa), 47 Wt. % formalin (300mL, 4.95 mole) was delivered at 10 mL/min. The reaction was stirred at130° C. for 60 min. after the formalin addition was complete. Then thereaction was cooled to 25° C., removed from the autoclave and assayed. A62% yield of (XVI) was observed.

[0222] C) A 1 L autoclave was charged with N-methylacetamide (IX) (160g, 2.2 mole), Co(OAc)₂.4H₂O (33 g, 0.13 mole), and acetic acid (1 L).After sealing the autoclave, 2200 psi (15,172 kPa) CO:H₂ (70:30) wasestablished at 25° C. with stirring at 2000 rpm. The contents of theautoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H₂ (70:30)was established. After approximately 0.5 h, rapid gas uptake wasobserved. The reaction mass was cooled to 85° C. Under a constant 3200psi (22,069 kPa), 47 Wt. % formalin (180 mL, 2.97 mole) was delivered at6 mL/min. The reaction was stirred at 85° C. for 30 min. after theformalin addition was complete. Then the reaction was cooled to 25° C.,removed from the autoclave, and assayed for N-acetylsarcosine. Thisresulted in a 92% yield of (XX).

[0223] D) A 1 L autoclave was charged with N-methylacetamide (IX) (90 g,1.23 mole), Co(OAc)₂.4H₂O (16.5 g, 0.13 mole), and tetrahydrofuran (500mL). After sealing the autoclave, 2200 psi (15,172 kPa) of CO:H₂ (70:30)was established at 25° C. with stirring at 2000 rpm. The contents of theautoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H₂ (70:30)was established. After approximately one hour, rapid gas uptake wasobserved. The reaction mass was cooled to 65° C. and the pressure wasslowly reduced to 1500 psi (10,345 kPa). At this point carbon monoxidewas established as the carboxymethylation feed gas. Under a constant1500 psi (10,345 kPa), 47 Wt. % formalin (180 mL, 2.97 mole) wasdelivered at 6 mL/min. The reaction was stirred at 65° C. for 30 min.after the formalin addition was complete. Then the reaction was cooledto 25° C., removed from the autoclave, and assayed for N-acetylsarcosine(XX). This resulted in an 85% yield of (XX).

[0224] E) A 2 L autoclave was charged with 1,3-dimethylurea (X) (96.9 g,1.1 mole), Co(OAc)₂.4H₂O (33 g, 0.13 mole), and acetic acid (500 mL).After sealing the autoclave, 2200 psi (15,172 kPa) CO:H₂ (70:30) wasestablished at 25° C. with stirring at 2000 rpm. The contents of theautoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H₂ (70:30)was established. After approximately 1 h, rapid gas uptake was observed.The reaction mass was cooled to 85° C. Under a constant 3200 psi (22,069kPa), 47 Wt. % formalin (201 mL, 3.31 mole) was delivered at 6 mL/min.The reaction was stirred at 85° C. for 60 min. after the formalinaddition was complete. Then the reaction was cooled to 25° C., removedfrom the autoclave, and concentrated to an oil under reduced pressure.The oil was treated with 2 L of 10% HCl at 100° C. for two hours. Thisresulted in a 5% yield of (XXIII).

[0225] F) A 1 L autoclave was charged with bis-(phosphonomethyl)urea(XII) (12.3 g, 0.05 mole), Co(OAc)₂.4H₂O (2.4 g, 0.01 mole), and aceticacid (300 mL). After sealing the autoclave, 2200 psi (15,172 kPa) CO:H₂(70:30) was established at 25° C. with stirring at 2000 rpm. Thecontents of the autoclave were heated to 130° C. and 3200 psi (22,069kPa) CO:H₂ (70:30) was established. After approximately 1.5 h, rapid gasuptake was observed. The reaction mass was cooled to 95° C. Under aconstant 3200 psi (22,069 kPa), 47 Wt. % formalin (10 mL, 0.17 mole) wasdelivered at 0.5 mL/min. The reaction was stirred at 95° C. for 60 min.after the formalin addition was complete. Then the reaction was cooledto 25° C., removed from the autoclave, and concentrated to an oil underreduced pressure. The oil was treated with 500 mL of 10% HCl at 100° C.for two hours. This resulted in a 5% yield of glyphosate (I).

[0226] G) A 300 mL autoclave was charged with N-acetylglycine(XVIII)(23.4 g, 0.20 mole), 95% paraformaldehyde (6.8 g, 0.22 mole),water (6.5 g, 0.36 mole), acetic acid (16.8 g, 0.28 mole), DME (90 mL),and Co₂(CO)₈ (2.01 g, 0.006 mole) and pressurized to 1500 psi (10,345kPa) CO:H₂ (95:5) at 25° C. This mixture was heated to 110° C. for 30min. HPLC analysis of this stream gave an 87% yield of (XVI), 1.0%(XIV), and 10% unreacted (XVIII).

[0227] H) A 2 L autoclave was charged with 130 g of a solid with acomposition of 85% methylene bisacetamide (VI)/10%[CH₃C(O)N(H)CH₂]₂NC(O)CH₃/5% acetamide (VII), Co(OAc)₂.4H₂O (49 g, 0.20mole), and THF (1 L). After sealing the autoclave, 2200 psi (15,172 kPa)of CO:H₂ (70:30) was established at 25° C. with stirring at 2000 rpm.The contents of the autoclave were heated to 130° C. and 3200 psi(22,069 kPa) CO:H₂ (70:30) was established. After approximately 0.5 h,rapid gas uptake was observed. Under a constant 3200 psi (22,069 kPa),47 Wt. % formalin (300 mL, 4.95 mole) was delivered at 10 mL/min. Thereaction was stirred at 130° C. for 60 min. after the formalin additionwas complete. Then the reaction was cooled to 25° C. and removed fromthe autoclave. HPLC analysis of the reaction indicated a 58% yield of(XVI).

[0228] I) A 2 L autoclave was charged with acetamide (VII)(128.5 g, 2.2mole), Co(OAc)₂.4H₂O (33 g, 0.13 mole), THF (960 mL), and acetic acid(40 mL). After sealing the autoclave, 2200 psi (15,172 kPa) of CO:H₂(70:30) was established at 25° C. with stirring at 2000 rpm. Thecontents of the autoclave were heated to 130° C. and 3200 psi (22,069kPa) CO:H₂ (70:30) was established. After approximately 75 min., rapidgas uptake was observed. The contents of the autoclave were cooled to85° C. and 3200 psi (22,069 kPa) was established with a CO:H₂(90:10)feed. Under a constant 3200 psi (22,069 kPa) (90:10/CO:H₂ feed), 47 Wt.% formalin (320 mL, 5.28 mole) was delivered at 9 mL/min. The reactionwas stirred at 85° C. for 60 min. after the formalin addition wascomplete. Then the reaction was cooled to 25° C., removed from theautoclave, and assayed for N-acetyliminodiacetic acid. This resulted ina 85% yield of (XVI) and 3% yield of (XVIII).

Example 16

[0229] This example illustrates one preferred mode of conducting thecarboxymethylation reaction where the formaldehyde is introduced in acontrolled fashion.

[0230] A 2 L autoclave was charged with acetamide (VII) (129.8 g, 2.2mole), THF (1 L), and acetic acid (45 g) and was purged with argon for10 min. Under the argon purge, Co₂(CO)₈ (20.9 g, 0.06 mole) was added.After sealing the autoclave, 150 psi (1034 kPa) of CO:H₂ (95:5) wasestablished at 25° C. and was slowly vented. Then 2200 psi (15,172 kPa)of CO:H₂ (95:5) was established at 25° C. with stirring at 2000 rpm. Thecontents of the autoclave were heated to 100° C. and 3200 psi (22,069kPa) CO:H₂ (95:5) was established. Under a constant 3200 psi (22,069kPa), 47 Wt. % formalin (320 mL, 5.28 mole) was delivered at 40 mL/min.The reaction was stirred at 100° C. for 52 min. after the formalinaddition was complete. Then the reaction was cooled to 25° C., removedfrom the autoclave, and assayed for N-acetyliminodiacetic acid. Thisresulted in a 95% yield of (XVI) and 1% glycine.

[0231] Examples 17-19

[0232] Examples 17-19 illustrate the profound effect the amount of waterpresent in the reaction has on (XVI) yield. Example 17 contains nowater; Example 18 contains 0.36 mole water; Example 19 contains 0.60mole water.

Example 17

[0233] A 300 mL autoclave was charged with acetamide (VII)(11.8 g, 0.2mole), 95% paraformaldehyde (13.6 g, 0.43 mole), acetic acid (10.6 g,0.18 mole, 0.12 9/mL of DME), DME (90 mL) and Co₂(CO)₈ (4.1 g, 0.012mole) and pressurized to 1500 psi (10,345 kPa) CO:H₂ (95:5) at 25° C.This mixture was heated to 125° C. for 30 min. HPLC analysis of thisstream indicated a 30% yield of (XVI) and a 47% yield of (XVIII).

Example 18

[0234] A 300 mL autoclave was charged with acetamide (VII)(11.8 g, 0.2mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (6.5 g, 0.36mole), acetic acid (16.8 g, 0.28 mol, 0.19 g/mL of DME), DME (90 mL) andCo₂(CO)₈ (4.1 g, 0.012 mole) and pressurized to 1500 psi (10,345 kPa)CO:H₂ (95:5) at 25° C. This mixture was heated to 125° C. for 30 min.HPLC analysis of this stream gave a 93% yield of (XVI), 1% (XIV), and 4%(XVIII).

Example 19

[0235] A 300 mL autoclave was charged with acetamide (VII)(11.8 g, 0.2mole), 95% paraformaldehyde (13.6 9, 0.43 mole), water (10.8 g, 0.60mole), acetic acid (16.8 g, 0.28 mole, 0.19 g/mL of DME), DME (90 mL)and Co₂(CO)₈ (4.1 g, 0.012 mole) and pressurized to 1500 psi (10,345kPa) CO:H₂ (95:5) at 25° C. This mixture was heated to 125° C. for 30min. HPLC analysis of this stream indicated a 91% yield of (XVI), 1%(XIV), and 3% (XVIII).

Example 20

[0236] This example illustrates the use of acetonitrile as a solvent.

[0237] A 300 mL autoclave was charged with acetamide (VII)(11.8 g, 0.2mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72mol), acetic acid (16.8 g, 0.28 mole), acetonitrile (90 mL) and Co₂(CO)₈(4.1 g, 0.012 mole) and pressurized to 3200 psi (22,069 kPa) CO:H₂(95:5) at 25° C. This mixture was heated to 110° C. for 30 min. HPLCanalysis of this stream indicated a 96% yield of (XVI), 1% (XIV), and 3%(XVIII).

Example 21

[0238] This example illustrates the use of acetone as a solvent.

[0239] A 300 mL autoclave was charged with acetamide (VII)(11.8 g, 0.2mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72mole), acetic acid (2.1 g, 0.035 mole), acetone (90 mL) and Co₂ (CO)₈(2.1 g, 0.006 mol) and pressurized to 3200 psi (22,069 kPa) CO:H₂ (95:5)at 25° C. This mixture was heated to 110° C. for 30 min. HPLC analysisof this stream indicated a 95% yield of (XVI), 0.5% (XIV), and 4.5%(XVIII).

Example 22

[0240] This example illustrates the utility of various reactionconditions for the carboxymethylation of acetamide (VII). Reactions wererun in a fashion similar to Example 1. Summarized in Table 5 are thereaction conditions employed and the results of those reactions. A 300mL autoclave was charged with 95% paraformaldehyde such that theparaformaldehyde to acetamide mole ratio was 2.15, 90 mL of solvent, andthe indicated amounts of acetamide, water, Co₂(CO)₈, and acetic acid.The autoclave was pressurized to the indicated pressure with CO:H₂(95:5) at 25° C. Each mixture was heated to 125° C. for 30 min. Analyseswere by HPLC. In the table, “DME” is dimethoxyethane, “THF” istetrahydrofuran and “HOAc” is acetic acid. TABLE 5 Percent yield of(XVI) based on starting amount of acetamide (VII) under differentreaction conditions. Ex- am- Pres- % ple sure Moles Water Moles MolesYield No. (psi) (VII) Solvent (g) Co₂(CO)₈ HOAc (XVI) 22.01 1500 0.4 DME25.8 0.0112 0.28 18 22.02 1500 0.4 DME 25.8 0.0226 0.28 47 22.03 15000.2 DME 12.9 0.0168 0.177 94 22.04 1500 0.2 DME 12.9 0.0119 0.28 9422.05 1500 0.2 DME 12.9 0.0116 0 90 22.06 1500 0.2 DME 12.9 0.0116 0.17793 22.07 1500 0.2 DME 12.9 0.0115 0.353 81 22.08 1500 0.2 DME 12.90.0114 0.3 98 22.09 1500 0.2 DME 12.9 0.0113 0.317 81 22.10 1500 0.2 DME12.9 0.0111 0.088 92 22.11 1500 0.2 DME 12.9 0.0093 0.28 72 22.12 15000.2 DME 12.9 0.0083 0.133 68 22.13 1500 0.2 DME 12.9 0.0056 0.088 4822.14 1500 0.2 DME 12.9 0.0056 0.177 44 22.15 1500 0.2 DME 10.8 0.01140.177 93 22.16 1500 0.2 DME 6.5 0.0114 0.28 60 22.17 1500 0.2 DME 4.30.0114 0.28 70 22.18 1500 0.2 DME 0 0.0113 0.28 30 22.19 1500 0.2Dioxane 12.9 0.0114 0.177 21 22.20 1500 0.1 DME 6.45 0.0056 0.177 9922.21 2200 0.4 DME 25.8 0.0236 0.28 56 22.22 2200 0.2 DME 12.9 0.01070.353 95 22.23 2500 0.2 THF 12.9 0.0114 0.28 92 22.24 2500 0.2 DME 12.90.0032 0.28 81 22.25 2500 0.2 DME 12.9 0.0061 0.28 99 22.26 2500 0.2Dioxane 12.9 0.0113 0.28 95 22.27 3200 0.2 Dioxane 12.9 0.0031 0.07  222.28 3200 0.2 Dioxane 12.9 0.0059 0.28 34 22.29 3200 0.2 HOAc 12.90.0112 1.552 45 22.30 3200 0.2 THF 12.9 0.0062 0.07 98 22.31 3200 0.2THF 12.9 0.0062 0.21 99 22.32 3200 0.2 THF 12.9 0.0035 0.072 97 22.333200 0.2 THF 12.9 0.0033 0 88 22.34 3200 0.2 THF 12.9 0.0031 0.28 9522.35 3200 0.2 THF 12.9 0.003  0.035 88 22.36 3200 0.2 THF 12.9 0.00290.14 94 22.37 3200 0.2 THF 12.9 0.0017 0.035  6 22.38 3200 0.4 DME 25.80.0234 0.57 83

Example 23

[0241] The tables contained in this example illustrate how certaincombinations of reaction conditions result in extremely high yields of(XVI). TABLE 6 Percent yield of (XVI) based on starting amount ofacetamide (VII) when HOAc/Co ratio is varied against moles H₂O. Reactionconditions included 1500 psi (10,345 kPa) CO:H₂ (95:5), 90 mL DMEsolvent, 11.8 g acetamide, 13.6 g of 95% paraformaldehyde, and 4.1 gCo₂(CO)₈. Parenthetical values represent Example Numbers from Table 5.Moles HOAc/Co Molar Ratio^(a) H₂O 15.179 15.55 23.607 24.585 24.64524.828 26.214 27.941 0    30 (22. 18) 0.239 70 (22. 17) 0.361 60 (22.16) 0.600 93 (22. 15) 0.717 93 94 98 81 (22. (22. (22. (22. 06) 04) 08)09)

[0242] TABLE 7 Percent yield of (XVI) based on starting amount ofacetamide (VII) when mmoles of acetic acid (HOAc) are varied againstmmoles of Co₂(CO)₈. Reaction conditions included 1500 psi (10,345 kPa)CO:H₂ (95:5), 90 mL DME solvent, 12.9 g water, 13.6 g of 95%paraformaldehyde, and 11.8 g acetamide. Parenthetical values representExample Numbers from Table 5. Mmol mmol Co₂(CO)₈ HOAc 5.6 5.7 8.3 9.311.1 11.3 11.4 11.5 11.6 11.9 16.8  0 90 (22. 05)  88 48 92 (22. (22.13) 10) 133 68 (22. 12) 177 44 93 94 (22. (22. (22. 14) 06) 03) 280 7294 (22. (22. 11) 04) 300 98 (22. 08) 317 81 (22. 09) 353 81 (22. 07)

[0243] TABLE 8 Percent yield of (XVI) based on acetamide (VII) whenacetic acid (HOAc) is varied against Co₂(CO)₈. Reaction conditionsinclude: 3200 psi (22,069 kPa) CO:H₂ (95:5), 90 mL THF solvent, 12.9 gwater, 13.6 g of 95% paraformaldehyde, and 11.8 g acetamide. Values inparenthesis represent example numbers from Table 5. Mmol Mmol Co₂(CO)₈HOAc 1.7 2.9 3.0 3.1 3.3 3.5 6.2  0 88 (22.33)  35 6 88 (22.37) (22.35) 70 98 (22.30)  72 97 (22.32) 140 94 (22.36) 210 99 (22.31) 280 95(22.34)

Example 24

[0244] This example illustrates the effect of pressure on the yields of(XVI) in the presence of acetic acid. TABLE 9 Reaction conditionsincluded CO:H₂ (95:5), 90 mL DME solvent, 12.9 g water, aceticacid-to-cobalt ratio of about 15:1 (based on cobalt atoms), 13.6 g of95% paraformaldehyde, and 11.8 g acetamide. Example numbers refer toexamples from Table 5. Mole % Cobalt in Reaction % Yield Example No.Pressure (psi) Mixture NAIDA 22.14 1500 6 44 22.25 2500 6 99 22.07 150012 81 22.22 2200 12 95

Example 25

[0245] This example illustrates how increasing the pressure in thecarboxymethylation reactions allows for dramatic increase in yield athigher reaction payloads. TABLE 10 Effect of pressure on percent yieldof (XVI) at various acetamide payload concentration. Reaction conditionsincluded 1500 or 3200 psi (22,069 kPa) CO:H₂ (95:5), 90 mL DME solvent,3.6 molar ratio of water-to-acetamide, about 15.0 molar ratio of aceticacid-to-cobalt atoms, and 13.6 g of 95% paraformaldehyde. Examplenumbers refer to examples from Table 5. Pressure Acetamide/DME % YieldExample No. Psi (g/6) NAIDA 22.38 3200 0.31 83 22.02 1500 0.31 47 22.071500 0.15 81 22.20 1500 0.075 99

Example 26

[0246] This example illustrates the effect that various solvents have onthe yield of (XVI). TABLE 11 Reaction conditions included CO:H₂ (95:5),90 mL solvent, 0.2 moles acetamide, 12.9 g water, and 13.6 g of 95%paraformaldehyde. Example numbers refer to examples from Table 5. %Example Pressure mmol mmol Yield No. Solvent (psi) Co₂ (CO) ₈ HOAc NAIDA22.19 Dioxane 1500 11.4 177 21 22.06 DME 1500 11.6 177 93 22.27 Dioxane3200 3.1 70 2 22.32 DME 3200 3.5 72 97

Example 27

[0247] This example illustrates how cobalt(II)bis-N-acetyliminodiacetate can be recovered from a typicalcarboxymethylation reaction mixture.

[0248] A) A 144.07 g quantity of a final carboxymethylation reactionmass was generated in a process similar to that described in Example 1.An autoclave was charged with acetamide (11.8 g, 0.2 mole), 95%paraformaldehyde (13.6 9, 0.43 mole), water (12.9 g, 0.72 mol), aceticacid (33.0 g, 0.55 mole), acetone (70 g), and Co₂(CO)₈ (2.55 g, 0.007mole) After sealing the autoclave, 150 psi (1034 kPa) of CO:H₂ (95:5)was established at 25° C. and was slowly vented. Then, 2200 psi (15,172kPa) CO:H₂ (95:5) was established at 25° C. with stirring at 2000 rpm.The contents of the autoclave were heated to 100° C. and 3200 psi(22,069 kPa) CO:H₂ (95:5) was established. This mixture was heated to100° C. for 30 min. Of this reaction mass, 141.3 g were transferred to around bottom flask. Air was bubbled through the stirred reaction mass atroom temperature for 130 min. until the solution turned dark purple witha slight cloudiness. The air supply was then turned off and the reactionmixture was heated at reflux for 80 min. Pink precipitate started toappear after 30 min. of heating and continued through the heatingperiod. The system was cooled to 30° C. and the pink solid was filtered,washed with acetone, and dried to give 5.89 g of solid. Analysis showedthe solid to contain 13.7% cobalt and 79.87% N-acetyliminodiacetic acid.Analysis of the liquid filtrate showed 242 ppm cobalt and 22.64%N-acetyliminodiacetic acid. Of the cobalt, 96.7% was in the pink solidand 3.3% was in the filtrate.

[0249] B) A 149.00 g quantity of a final carboxymethylation reactionmass was generated in a process similar to that described in Example 1.An autoclave was charged with acetamide (11.8 g, 0.2 mole), 95%paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72 mol), aceticacid (33.0 g, 0.55 mol), acetone (70.1 g), and Co₂(CO)₈ (3.03 g, 0.009mole). After sealing the autoclave, 150 psi (1034 kPa) CO:H₂ (95:5) wasestablished at 25° C. and was slowly vented. Then, 2200 psi (15,172 kPa)of CO:H₂ (95:5) was established at 25° C. with stirring at 2000 rpm. Thecontents of the autoclave were heated to 100° C. and 3200 psi (22,069kPa) CO:H₂ (95:5) was established. This mixture was heated to 100° C.for 30 min. Of this reaction mass, 143.9 g was transferred to a roundbottom flask. Air was bubbled through the stirred reaction mass while itwas brought to 61.5° C. It was held there for 120 min. while airbubbling continued. The solution was clear and dark red to purple after40 min. and pink precipitate first appeared after 60 min. The system wascooled to 30° C. and the pink solid was filtered off, washed withacetone, and dried to give 6.59 g solid. Analysis of the solid showed13.4% cobalt and 78.97% N-acetyliminodiacetic acid. Analysis of theliquid filtrate showed 215 ppm cobalt and 20.63% N-acetyliminodiaceticacid. Of the cobalt, 97.2% was in the pink solid and 2.8% was in thefiltrate.

[0250] C) In a typical carboxymethylation reaction, a 300 mL autoclavewas charged with a mixture of water (12.9 g), glacial acetic acid (33.0g), acetone (90 mL), paraformaldehyde (13.6 g of 95+% powder), acetamide(11.8 g), and Co₂ (CO)₈ (4.109 g, equivalent to ca. 1416 mg cobalt). Agas mixture of CO:H₂ (95:5)was charged at an initial pressure of 3200psi (22,069 kPa), the reactor was heated to 110° C. for 30 min. withstirring, and then cooled to below 20° C. The pressure was slowlyvented, the system purged with nitrogen (N₂), and the reactor was sealedup. The contents were heated with stirring (closed system) to 90° C.,stirred at 90° C. for 3 h, and then cooled to 20° C. The pressure in thereactor, after cooling, was 160 psi (1103 kPa). The pressure wasreleased, the reactor opened, and the contents filtered to obtain 8.44 gof pink powder containing 11.8% cobalt(996 mg; 70% of cobalt used). Themother liquors were found to contain 203 mg cobalt. Some solids adheredto the reactor. These were removed by dissolution in water and found tocontain 267 mg of cobalt.

[0251] D) In a typical carboxymethylation reaction, a 300 mL autoclavewas charged with a mixture of water (12.9 g), glacial acetic acid (33.0g), tetrahydrofuran (90 mL), paraformaldehyde (13.6 g of 95+% powder),acetamide (11.8 g), and C₂ (CO)₈ (2.078 g, equivalent to ca. 716 mgcobalt). A gas mixture of CO:H₂ (95:5) was charged at an initialpressure of 3200 psi (22,069 kPa), the reactor heated to 110° C. for 30min. with stirring, and then cooled to below 20° C. The pressure wasslowly vented, the system purged with N₂, and the reactor was openedunder an inert atmosphere and its contents transferred to a 250 mL glassthree-necked round bottom flask fitted with a gas inlet tube, athermocouple thermometer, and a distillation head. The vessel was heatedunder a N₂ atmosphere and the contents distilled (pot temp.−70-80° C.,still head temp−64° C.) until ca. 60 mL distillate was collected. Pinkprecipitate formed in the bottoms during the distillation. Aftercooling, the bottoms were filtered to obtain 4.96 g of pink powdercontaining 12.0% cobalt(596 mg; 83% of cobalt used). The mother liquorswere found to contain 13 mg cobalt. Some solids adhered to thedistillation flask. These were removed by dissolution in water and foundto contain 37 mg of cobalt.

Example 28

[0252] This example illustrates the conversion of (XVI) to a mixture of(XVII) under various reaction conditions.

[0253] N-acetyliminodiacetic acid (XVI) monohydrate (45 g) and varyingamounts of water and acetic acid were heated at 175° C. or 195° C. forvarious periods of time. After cooling to room temperature, the mixturewas filtered. The solid was washed with water (10 mL) and dried to give1,4-di (carboxymethyl) -2,5-diketopiperazine. The table below shows theyields of solid under various conditions. TABLE 12 Added Total TotalIsolated Isolated Added acetic DKP IDA DKP IDA Temp. Time water acid(XVII) (XIV) (XVII) (XIV) Ex. (C.) (min) (g) (g) (g) (g) (g) (g) 28.1175 90 0 10 22.98 0.85 22.66 0.00 28.2 175 20 0 10 19.26 1.76 19.02 1.2128.3 175 45 0  0 23.71 0.69 23.40 0.00 28.4 175 20 5 10 18.66 3.37 18.252.52 28.5 195 45 0 10 23.98 0.36 23.56 0.00 28.6 195 45 5  0 24.78 0.2924.04 0.00 28.7 195 45 5 10 23.74 0.83 23.31 0.00 28.8 195 20 5 10 23.150.92 22.69 0.00 28.9 195  5 5 10 21.29 1.23 20.83 0.00

Example 29

[0254] This example illustrates that the amount of either (XVII) or(XIV) obtained from (XVI) can vary depending on the reaction conditions.

[0255] N-acetyliminodiacetic acid (XVI) monohydrate (10 g), acetic acid(5 g), and water (35 g) were heated to 150° C. in an autoclave. Table 13shows the relative amounts of products based on ¹H NMR analysis atvarious times. TABLE 13 % NAIDA % DKP % IDA Hours (XVI) (XVII) (XIV) 0100   0  0 0.5 35  3 57 2  6 19 74 4  5 27 68

Example 30

[0256] This example illustrates the conversion of N-acetyliminodiaceticacid (XVI) to iminiodiacetic acid (XIV) in the presence of a mineralacid.

[0257] A) N-acetyliminodiacetic acid (XVI) monohydrate (8.45 g) and 9 NHCl (11 g) were heated under reflux for 30 min. Analysis of the mixtureshowed 99% conversion to iminodiacetic acid hydrochloride. Aftercooling, the mixture is filtered and the solid is dried to giveiminodiacetic acid hydrochloride.

[0258] B) A mixture of 30% H₂SO₄, 30% H₂O and 40% NAIDA XVI (by weight)was heated in a 110° C. oil bath for 20 min. Analysis of the mixtureshowed that hydrolysis to iminodiacetic acid (XIV) was complete.

Example 31

[0259] This example illustrates the preparation ofN-(phosphonomethyl)iminodiacetic acid (XV) from N-acetyliminodiaceticacid (XVI) monohydrate.

[0260] N-acetyliminodiacetic acid (XVI) monohydrate, sulfuric acid,water, and phosphorus acid were heated to 110° C. and 42% formalin (6.5mL, 0.10 mole) was added over a one hour period. After another 1.75hours at 110° C. the mixture was cooled and filtered. The solid waswashed and dried to give N-(phosphonomethyl)iminodiacetic acid (PMIDA).All reactants/solvents appear in the table below along with the amountof PMIDA (XV) produced. Unless otherwise noted, the amount of H₃PO₃ is11.39 g (0.14 mole). TABLE 14 Phosphonomethylations of (XVI) NAIDA (XIV)H₂CO, ca. H₂SO₄ Wet PMIDA 92% 42% 98% H₂O Solid (XV) (g) (mL) (g) (g)(g) (g) 17.5 8.60 10 10 23.90 22.09 17.5 8.60 15 10 22.23 17.4 3.64 1525 21.43 19.36 17.4 8.60 10 10 20.55 18.79 17.4 8.60 15  5 21.65 16.1719.0 6.50 15  5 25.43 20.37 17.0 5.85 15  5 21.45 15.09 17.0 5.85 15  514.98 12.46 19.0 5.85 15  5 18.37 14.47 19.0 4.85 15  5 15.71 13.19

Example 32

[0261] This example illustrates the preparation (XV) from1,4-di(carboxymethyl)-2,5-diketopiperazine (XVII).

[0262] A) 1,4-di(carboxymethyl)-2,5-diketopiperazine (XVII) (0.8059 g),water (0.51 g), 12N HCl (4.25 g) and 47.4% formalin (0.5342 g) wereheated in a sealed tube in a 105° C. oil bath with stirring for one hourthen heated at 105° C. for one hour to yield 55% of (XV).

[0263] B) 1,4-di(carboxymethyl)-2,5-diketopiperazine (11.9 9),phosphorus trichloride hydrolysate (43.8% H₃PO₃, 16.8% HCl, 26 g) and20% HCl (26 g) were heated to 120° C. and formalin (8.4 g, 47.42%) wasadded over a 30 min. period. The solution was held at 120° C. for 1.75 hto yield 88.2% of (XV).

Example 33

[0264] This example illustrates the direct preparation of (I) from(XVIII).

[0265] A 1 L flask was charged with N-acetylglycine (XVIII) (117.0 g,1.0 mole), acetic acid (100 mL), and water (18 g, 1.0 mole). Phosphorustrichloride(137 g, 1.0 mole) was slowly added at 25° C. with rapidstirring. The temperature of the reaction mass quickly warmed to 50° C.during this time. Then at 45° C., 47 Wt. % formalin (60 mL, 1.03 mole)was added over 0.5 h. The solution was maintained at 75° C. for 19 hafter the addition of formalin. Assay of the reaction at this timeindicated a 15% yield of glyphosate (I).

Example 34

[0266] This example illustrates the conversion of (XVII) to (XIV) in thepresence of mineral acid under various conditions.

[0267] 1,4-di(carboxymethyl)-2,5-diketopiperazine (XVII) (1 g) washeated under reflux in aqueous 1N, 3N, 6N, 9N, and 12 N HCl. The tablebelow shows the percent of (XVII) remaining at various times. Thehydrolysis product was shown by NMR to be mostly (XIV). TABLE 15 Percent(XVII) Remaining Min. 12N 9N 6N 3N 1N  5 80.12 86.49 93.71 100  10 67.0789.11 84.95 94.7 98.96  20 58.7 70.74 72.51 87.94 98.77  40 36.65 56.2564.25 87.14 98.65  80 22.36 32.1 46.1 79.01 98.62 160 9.93 14.44 29.0378.92 98.79 320 3.25 5.13 68.95 97.13 640 37.39 97.36 1280  24 2720 5.96 6970  75.78

Example 35

[0268] These examples illustrate the conversion of (XX) to (XXI).

[0269] A) N-acetyl sarcosine (XX) (20.0 g, 152.5 mmole), phosphorousacid (12.5g, 152.4 mmole), and concentrated HCl (37.6 g) were mixed andrefluxed in a 120° C. oil bath. Formalin, 37% (13.6 g, 167.6 mmole) wasadded dropwise over 20 min. and the reaction was continued for anadditional 19 h. HPLC analysis indicated a 99% yield ofN-methylglyphosate (XXI) based on moles of (XX) charged.

[0270] B) Per conditions described in (A), N-propionylsarcosine (20.0 g,137.8 mmole) was converted into N-methylglyphosate using phosphorousacid (11.3 g, 137.8 mmole), concentrated hydrochloric acid (10.0 g), and12.3 g of 37% formalin (152.1 mmole). HPLC analysis indicated a 96.6%yield of N-methylglyphosate (XXI) based on moles of N-propionylsarcosinecharged.

[0271] C) Per conditions described in (A), sarcosine anhydride (XXV)(2.06 g, 14.50 mmole) was converted into N-methylglyphosate (XXI) usingphosphorous acid (2.38 g, 29.02 mmole), concentrated hydrochloric acid(5.7 g), and 2.6 g of 37% formalin (32.0 mmole). HPLC analysis indicateda 97.2% yield of (XXI) based on mmoles of (XXV) charged.

[0272] D) N-acetyl sarcosine (XX)(2.0 g, 15.3 mmole), phosphorous acid(1.25 g, 15.3 mmole) were mixed with concentrated sulfuric acid (3.1 9)and water (1.7 g) then refluxed in a 120° C. oil bath. Formalin, 37%(1.4 g, 16.7 mmole) was added dropwise over 20 min. and the reaction wascontinued for an additional 18 h. ³¹p NMR analysis indicated 98% yieldof (XXI) based on mmoles of (XX) charged.

Example 36

[0273] This example illustrates the conversion of sarcosine (XXIII) to(XXI).

[0274] Sarcosine (XXIII) (89.09 g, 1.00 mole), phosphorous acid (82.0 g,1.0 mole) and concentrated hydrochloric acid (110 g) were mixed andrefluxed in a 130° C. oil bath. Formalin, 37% (89.3 g, 1.1 mole) wasadded dropwise over 20 min. and the reaction was continued for anadditional 85 min. At this point, ³¹p NMR indicated the followingproduct distribution (on a molar basis): N-methyl glyphosate (89.9%),phosphorous acid (2.1%), phosphoric acid (1.9%), hydroxymethylphosphorous acid (0.4%), and an unknown product (5.7%; NMR: triplet,8.59 ppm). After cooling to room temperature, 40 g (1 mole) sodiumhydroxide was added followed by 250 g water leading to the formation ofa white precipitate which was recovered by filtration and assayed byHPLC. The total recovered yield of N-methylglyphosate was 70.5% based onthe amount of sarcosine and phosphorous acid used.

Example 37

[0275] This example illustrates the conversion of an N-methylglyphosate(XXI) to glyphosate (I) using a platinum catalyst and oxygen.

[0276] A) N-methylglyphosate (XXI) (10.0 g), 140 g water, and 1 gplatinum black (Aldrich Chemical) were combined in a round bottom flaskand equipped with a water-cooled reflux condenser immersed in a 150° C.oil bath. Oxygen was bubbled through the reaction mixture for four hoursas the solution was stirred. At the end of this period, HPLC analysisrevealed the following product distributions (on a molar basis):glyphosate (I) (86.4%), N-methylglyphosate (XXI) (8.7%),aminomethylphosphonic acid (2.2%) and phosphoric acid (2.7%). Glyphosate(I) precipitated from the solution after cooling to room temperature.

[0277] B) A mixture of N-methylglyphosate (XXI) (10.0 g), platinum black(2.0 g) and sufficient water to bring the total volume of the mixture to200 ml, was stirred for two hours and 40 min. at a temperature of 80° C.while oxygen at a pressure of 1 atm. was bubbled through the reactionmixture. Analysis of the reaction mixture indicated the followingproduct distribution (on a molar basis): N-methylglyphosate (XXI)- notdetected; glyphosate (I) (85.4%); phosphoric acid (8.1%). The othercomponents of the reaction mixture were unidentified.

Example 38

[0278] This example illustrates the conversion of N-isopropylglyphosateto glyphosate (I) using a platinum (Pt) catalyst and oxygen.

[0279] N-isopropylglyphosate (1.0 g), 10 g water, and 0.3 g platinumblack (Aldrich) were combined in a round bottom flask equipped with awater-cooled reflux condenser and immersed in an 80° C. oil bath. Astream of oxygen was introduced at the reaction surface for 18 hours asthe solution was stirred. At the end of this period, ³¹p NMR indicatedthe following product distribution (on a molar basis): glyphosate (I)(91%), amino phosphonic acid (1%), phosphoric acid (6%), and an unknownproduct (2%; 15.0 ppm). Glyphosate (I) precipitated from solution aftercooling to room temperature.

Example 39 Cobalt Precipitation by Anaerobic Oxidation—Reflux Method

[0280] In a typical carboxymethylation reaction, a 300-mL autoclave wascharged with a mixture of distilled deionized water (12.9 g), glacialacetic acid (33.0 g), tetrahydrofuran (90 mL), paraformaldehyde (13.6 gof 95+% powder), acetamide (11.8 g), and cobalt tetracarbonyl dimer(2.105 g, equivalent to ca. 726 mg Co). A gas mixture of 95:5 CO:H2 wascharged at an initial pressure of 3200 psi, the reactor was heated to110° C. for 30 minutes with stirring, and then cooled to below 20° C.The pressure was slowly vented, the system purged with N2, and thereactor was opened under an inert atmosphere and its contentstransferred to a 250-mL glass 3-necked round-bottomed flask fitted witha gas inlet tube, a thermocouple thermometer, and a distillation head.The vessel was heated at reflux under a N2 atmosphere for 3 hours. Pinkprecipitate formed during heating. After cooling, the mixture wasfiltered to obtain 5.62 g of pink powder containing 12.6% cobalt (708mg; 98% of cobalt used). The mother liquors were found to contain 13 mgcobalt(2% of cobalt used).

Example 40

[0281] This example illustrates the improved selectivities which may beachieved in the oxidative dealkylation of an N-alkyl amino acid reactionproduct when an electroactive molecular species is adsorbed to a noblemetal catalyst. All of the electroactive molecular species adsorbed toplatinum black in this example undergo oxidation and reduction byelectron transfer. Thus, the treatment of platinum-containing catalystsby both electroactive molecular species and their oxidative precursorsis exemplified herein.

[0282] This experiment was conducted by heating to reflux a mixturecontaining 1 g of N-(phosphonomethyl)-N-methyl-glycine XXI (“NMG”), 20ml water, and 50 mg of platinum metal in a magnetically-stirred,round-bottom flask equipped with a reflux condenser. Oxygen was bubbledthrough for 5 hours using a needle. The catalyst was then removed byfiltration and the filtrate analyzed by HPLC.

[0283] To prepare the organic-treated catalysts, 0.5 g of platinum black(Aldrich Chemical Co., Inc., Milwaukee, Wis.) was added to a solution of25 mg of the poison (i.e., the electroactive molecular species) in 50 mlof anhydrous acetonitrile. The mixture sat capped in an Erlenmeyer flaskfor four days, except that the 4,4′-difluorobenzophenone catalyst onlywas exposed to solution for one day. The catalyst subsequently wasrecovered by filtration, rinsed with acetonitrile and diethyl ether, andair-dried overnight.

[0284] The 2,4,7-trichlorofluorene catalyst was prepared using 0.3 g ofPt black and 30 ml of a solution consisting of 834.5 ppm2,4,7-trichlorofluorene in acetonitrile/1% CH₂Cl₂ solution (used tofacilitate dissolution of the electroactive molecular species) which wasallowed to evaporate at room temperature. The catalyst subsequently waswashed with ethanol and air-dried. The inorganic-treated catalysts wereprepared by combining 0.50 g of Pt black, 50 ml of tetrahydrofuran, andeither 25 or 100 mg of the inorganic electroactive molecular species,and stirring overnight at room temperature in a sealed 125 ml Erlenmeyerflask. The catalyst was recovered by filtration, washed with diethylether, and air-dried overnight.

[0285] The inorganic species used, all of which are available fromAldrich Chemical (Milwaukee, Wis.), were:

[0286] 1. 5,10,15,20-tetrakis (pentafluorophenyl)-21H,23H-porphine iron(III) chloride (abbreviated “Fe(III)TPFPP chloride” in Table 16).Approximately 25 mg was used to prepare the catalyst.

[0287] 2. 5,10,15,20-tetraphenyl-21H,23H-porphine iron (III) chloride(abbreviated “Fe(III) TPP chloride” in Table 16). Approximately 25 mgwas used to prepare the catalyst.

[0288] 3. 5,10,15,20-tetraphenyl-21H,23H-porphine nickel (II)(abbreviated as “Ni(II) TPP” in Table 16). Approximately 25 mg was usedto prepare the catalyst.

[0289] 4. Ruthenium-tris(2,2′-bipyridine) dichloride (abbreviated as“[Ru(bpy)₃]C1 ₂” in Table 16). Approximately 100 mg was used to preparethe catalyst.

[0290] 5 Ferrocene. Approximately 100 mg was used to prepare thecatalyst.

[0291] Where available, literature data on the oxidation potential(E_({fraction (12)})) of the electroactive molecular species is reportedin Table 16. This example illustrates that electroactive molecularspecies being relatively soluble in water (e.g., ferrocene and[Ru(bpy)₃]Cl₂) are less effective at enhancing glyphosate selectivity.This example also demonstrates that hydrophobic electroactive molecularspecies increase the catalyst's selectivity. Electroactive molecularspecies having oxidation potentials more negative than about +0.3 V vsSCE generally decrease conversion. Thus, the preferred electroactivemolecular species for enhancing the selectivity and conversion of NMGoxidation may be either organic or inorganic, but should be hydrophobicand have oxidation potentials more positive than about 0.3 volts vs.SCE. TABLE 16 Use of Electroactive Molecular Species on NMG OxidationMAMPA H₃PO₄ E_(½) Conv. Glyphosate Select Select Poison V vs SCE (%)Select (%) (%) (%) None — 45.7 83.1 9.0 7.95 2,4,7-trichloro- ? 52.993.5 2.5 4.0 fluorene N-hydroxy- +1.44 56.3 93.2 2.4 4.4 phthalimidetris(4-bromo- +1.05 35.3 93.5 2.5 4.0 phenyl)amine TEMPO +0.6  71.2 92.92.4 4.6 Triphenyl- +0.27 22.1 93.4 ˜0 6.6 methane 4,4′-difluoro- ? 8.691.4 ˜0 10.9 benzophenone Fe (III) TPFPP +0.07 22.9 89.7 4.0 6.3chloride Fe (III) TPP +1.11 69.3 91.1 2.6 6.3 chloride Ni (II) TPP +1.1553.8 90.3 2.9 6.8 [Ru(bpy)₃]Cl₂ +1.32 37.9 68.9 12.1  19.1 Ferrocene +0.307 70.8 82.6 6.0 11.4

Example 41

[0292] This example illustrates the effect of electroactive molecularspecies on the platinum-catalyzed oxidation of N-isopropyl glyphosateusing the commercially available catalyst 20% Pt on Vulcan XC-72R carbon(manufactured by Johnson-Matthey and available from Alfa/Aesar (WardHill, Mass.). The commercial catalyst was tested along with a catalystwhich had been impregnated with two electroactive molecular species:N-hydroxyphthalimide and triphenylmethane.

[0293] These catalysts were used to oxidize N-isopropyl glyphosate bythe method described in the previous example. Approximately 1 g ofN-isopropyl glyphosate was substituted forN-(phosphonomethyl)-N-methyl-glycine XXI. The results shown in Table 17demonstrate that electroactive molecular species improve the selectivityof platinum on carbon catalysts for this reaction. Modifiers with lesspositive oxidation potentials such as triphenylmethane appear to be moreeffective than those with more positive oxidation potentials, such asN-hydroxyphthalimide. This example also demonstrates that the use ofgraphitic supports for platinum is less effective in suppressingundesired side reactions in N-isopropyl glyphosate oxidations than isthe case for N-(phosphonomethyl)-N-methyl-glycine XXI. TABLE 17 Use ofElectroactive Molecular Species During Oxidation of N-IsopropylGlyphosate E_(½) Conv. Glyphosate MAMPA H₃PO₄ Catalyst V vs SCE (%)Select (%) Select (%) Select (%) Platinum — 77.0 79.8 8.9 11.3 black 20%Pt/ +0.07 81.9 20.5 72.1 7.4 Vulcan XC-72R carbon (25 mg used) 20% Pt/+1.44 41.2 31.6 62.1 6.2 Vulcan treated with N-hydroxy- phthalimideloading 35.3 mg/g (26 mg used) 20% Pt/ +0.27 60.2 50.1 25.4 24.5 Vulcantreated with triphenyl- methane loading 305 mg/g (32.6 mg used)

Example 42

[0294] This example demonstrates the selectivities that may be achievedwhen N-alkyl glyphosates are oxidized at low rates of oxygen deliveryand moderate conversion if an electroactive molecular species such asTEMPO (i.e., 2,2,6,6-tetramethyl piperidine N-oxide) is added to thereaction mixture. No pretreatment of the catalyst is required. Thisexample further demonstrates that the conversion improves over the firstfew cycles when the electroactive molecular species is added to themixture. Finally, this example demonstrates that the electroactivemolecular species reduces the amount of noble metal loss.

[0295] A 300 ml glass pressure bottle was equipped with a thermocoupleand two fritted filters. One of the filters located about half an inchabove the center of the bottom of the bottle was used for gasdispersion. The second filter, located about an inch from the bottom andnot centered, was used for the withdrawal of liquids. A gas exit lineleading to a back pressure regulator set to maintain the pressure at 50psig also was provided. Approximately 60 g ofN-(phosphonomethyl)-N-methyl-glycine XXI, 180 ml of water, 3 g ofplatinum black (Aldrich Chemical, Milwaukee, Wis.), and 40 mg of TEMPOdissolved in 1 ml of acetonitrile were combined in the pressure reactor.The mixture was heated to 125EC while stirring under a 50 psig nitrogenatmosphere, forming a homogeneous mixture. A nitrogen/oxygen mixture(75% nitrogen, 25% oxygen by volume) was bubbled through for 90 minutesat a flow rate of 1 slpm while the pressure was maintained at 50 psig.The reaction mixture then was withdrawn through a fritted filter,leaving the catalyst behind. Another 60 g ofN-(phosphonomethyl)-N-methyl-glycine XXI, 180 ml of water, and 40 mg ofTEMPO in 1 ml of acetonitrile subsequently was added to the flask andthe cycle repeated. Four cycles in all were performed. In all cases,(M)AMPA concentrations were below the quantifiable limits, althoughtraces were detected. The only quantifiable by-product detected wasphosphoric acid. The conversions and selectivities at the end of each ofthe four cycles are shown in Table 18.

[0296] The concentration of dissolved platinum was determined at the endof each run by inductively-coupled plasma mass spectrometry. Thisdissolved platinum concentration was less than 0.1 ppm in cycles 2, 3,and 4. This is lower than the concentration of platinum that wasobserved (i.e., 0.3 to 1.1 ppm) when platinum black was used without thepresence of an electroactive molecular species under similar reactionconditions over 7 cycles. Although a higher amount of platinum leachedinto solution during the first cycle (i.e., the dissolved platinum was8.3 ppm), it is believed that most of the lost platinum was primarilyunreduced platinum on the platinum black's surface. In fact, the samephenomenon occurred when platinum black was used without anelectroactive species; in that instance the concentration of dissolvedplatinum was 4.2 ppm. TABLE 18 Oxidation of NMG XXI in the Presence ofTEMPO at 125EC for 90 Min. Cycle Conversion Glyphosate H₃PO₄ SelectivityNumber (%) Selectivity (%) (%) 1 32.6 98.3 1.7 2 38.0 98.1 1.9 3 43.398.1 1.9 4 46.2 97.3 2.7

[0297] In view of the above, it will be seen that the several objects ofthe invention are achieved and other advantageous results attained.

[0298] As various changes could be made in the above methods withoutdeparting from the scope of the invention, it is intended that allmatter contained in the above description or shown in the accompanyingdrawings shall be interpreted as illustrative and not in a limitingsense.

What is claimed is:
 1. An acetamide equivalent compound selected fromthe group consisting of compounds having the formula:

wherein R¹³ and R¹⁴ are independently hydrogen, hydroxymethyl, alkyl,carboxymethyl, phosphonomethyl, or an ester or salt of carboxymethyl orphosphonomethyl; R^(15,) R¹⁶ and R¹⁷ are independently alkyl or —NR³R⁴;and R³ and R⁴ are independently hydrogen, hydrocarbyl, or substitutedhydrocarbyl.
 2. The compound of claim 1 wherein R¹³, R¹⁴ R^(15,) R¹⁶ andR¹⁷are independently methyl, ethyl or isopropyl.
 3. The acetamideequivalent compound of claim 1, wherein R¹⁵ and R¹⁶ are methyl.
 4. Theacetamide equivalent compound of claim 1, wherein the acetamideequivalent compound has the formula:


5. The acetamide equivalent compound of claim 4, wherein R¹⁵ and R¹⁶ aremethyl.
 6. The acetamide equivalent compound of claim 4, wherein R¹⁵ andR¹⁶ are ethyl.
 7. The acetamide equivalent compound of claim 4, whereinR¹⁵, R¹⁶, and R¹⁷ are methyl.
 8. The acetamide equivalent compound ofclaim 4, wherein R¹⁵, R¹⁶, and R¹⁷ are ethyl.
 9. The acetamideequivalent compound of claim 1, wherein the acetamide equivalentcompound has the formula:


10. The acetamide equivalent compound of claim 9, wherein R¹⁵ and R¹⁶are methyl.
 11. The acetamide equivalent compound of claim 9, whereinR¹³, R¹⁴, R¹⁵ and R¹⁶ are methyl.
 12. The acetamide equivalent compoundof claim 9, wherein R¹³, R¹⁴, R¹⁵, and R¹⁶ are ethyl.
 13. The acetamideequivalent compound of claim 9, wherein R¹³ and R¹⁴ are hydrogen; andR¹⁵ and R¹⁶ are methyl.
 14. The acetamide equivalent compound of claim9, wherein R¹³ and R¹⁴ are hydrogen; and R¹⁵ and R¹⁶ are ethyl.
 15. Acompound having the formula:

wherein R¹ is hydrogen, hydrocarbyl, substituted hydrocarbyl, —NR³R⁴, or—SR⁶; R³ and R⁴ are independently hydrogen, hydrocarbyl, or substitutedhydrocarbyl; and R⁶ is hydrogen, hydrocarbyl, substituted hydrocarbyl,or a salt-forming cation.
 16. The compound as set forth in claim 15,wherein R¹ is methyl.
 17. The compound as set forth in claim 93, whereinR¹ is —NR³R⁴.